Interplay between Mitophagy and Inflammasomes in Neurological

Mitophagy and inflammasomes have a pivotal role in the development of ... Along with it, inflammasome activation also plays a major role, which is usu...
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Interplay between Mitophagy and inflammasome in Neurological Disorders Radhika Kesharwani, Deepaneeta Sarmah, Harpreet Kaur, Leela Mounika, Geetesh Verma, Veeresh Pabbala, Vignesh Kotian, Kiran Kalia, Anupom Borah, Kunjan R. Dave, Dileep R Yavagal, and Pallab Bhattacharya ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.9b00117 • Publication Date (Web): 27 Mar 2019 Downloaded from http://pubs.acs.org on March 27, 2019

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ACS Chemical Neuroscience

Interplay between Mitophagy and inflammasome in Neurological Disorders

2 3

Radhika Kesharwani1†, Deepaneeta Sarmah1†, Harpreet Kaur1, Leela Mounika1,

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Geetesh Verma1, Veeresh Pabbala1, Vignesh Kotian1, Kiran Kalia1, Anupom Borah2,

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Kunjan R Dave3, Dileep R Yavagal3 and Pallab Bhattacharya1*

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1Department

of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.2 Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.3Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.

†Authors

have equal contribution

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*Address of correspondence:

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Pallab Bhattacharya, Ph.D Assistant Professor, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar-382355, Gujarat, India. Email: [email protected] [email protected] Phone: +91 79 66745555 Fax: +91 79 66745560

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List of Abbreviations

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NLR - Nucleotide-binding oligomerization domain (NOD)-like receptors

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ASC-Apoptosis speck-like protein containing a caspase recruitment domain (CARD)

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NLRP3 – NLR family pyrin domain containing protein 3

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NLRP1 - NLR family pyrin domain containing protein 1

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NLRC4 - NLR family CARD domain containing protein 4

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Atg– Autophagy related genes

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ULK1 – Unc 51 like autophagy activating kinase 1

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LC3 – Light chain kinase 3

10

GABARAP – GABA type A receptor associated protein

11

ROS – Reactive Oxygen Species

12

Bnip3 – BCL 2 interacting protein 3

13

FUNDC1 - FUN14 domain-containing protein 1

14

CK2 – Casein kinase 2

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DRP1 – Dynamin related protein 1

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OPA1 – Mitochondrial dynamin like GTPase

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OMM – Outer mitochondrial membrane

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IMM – Inner mitochondrial membrane

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PINK1 - PTEN-induced putative kinase

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CCCP – Carbonyl cyanide m-chlorophenyl hydrazone

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MMP – Mitochondrial membrane potential

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BAK - Bcl2 associated athano genes

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PLEKHM1 - Pleckstrin homology domain containing protein family member 1

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AMBRA – Autophagy and beclin 1 regulator 1

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TAXBP1-Tax1-binding protein 1

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SQSTM1-Sequestosome 1

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NBR1-Neighbor of BRCA1 gene 1

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PARL- Presenilin Associated Rhomboid Like

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PTEN-L-Phosphatase and tensin homolog-L 2 ACS Paragon Plus Environment

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ASC-Apoptosis-Associated Speck-like Protein

2

CIITA-Class II Major Histocompatibility Complex Transactivator

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IPAF-ICE-Protease Activating Factor

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NAIP-NLR Family Apoptosis Inhibitory Protein

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CARD-Caspase recruitment domains

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ASIC- Acid-sensing ion channel 1

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AMPK- AMP-activated protein kinase

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MAPK- Mitogen-activated protein kinase

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NFKB- Nuclear factor kappa-light-chain-enhancer of activated B cells)

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Nrf2- Nuclear factor (erythroid-derived 2)-like 2

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MFF- MITOCHONDRIAL FISSION FACTOR;

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Trx1-Thioredoxin-1

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APC-Antigen presenting cell

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NR4A1- Nuclear Receptor Subfamily 4 Group A Member 1

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JNK - C-Jun N-terminal kinase

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TLR4-Toll-like receptor-4

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ANSCs- Adult neural stem cells

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SVZ-Sub-ventricular zone

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PPAR- Peroxisome proliferator-activated receptors

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PGC1-α- Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

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DFCP1- Double FYVE-containing protein 1

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PTM-Post-translational modifications

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TBK1- Serine/Threonine-Protein Kinase-1

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VCP-Valosin-containing protein

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HLA-Human leukocyte antigen

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MttHtt- Mutant huntigtin gene

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CCL4- C-C motif chemokine 4

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IGF-1- Insulin-like growth factor 1

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HMGB-1- High mobility group box 1 protein 3 ACS Paragon Plus Environment

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PGF-2α - Prostaglandin F2α

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I-FABP- Fatty Acid Binding Protein 1

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DAMP- Damage-associated molecular patterns

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PAMP-Pathogen-associated molecular patterns

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Wdfy3- WD Repeat and FYVE Domain Containing 3

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NOS- Nitric oxide synthase

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Abstract

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Mitophagy and inflammasome have a pivotal role in the development of

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neuropathology. Molecular mechanisms behind mitophagy and inflammasome are

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well understood, but lacunae prevail in understanding the crosstalk between them in

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various neurological disorders. As mitochondrial dysfunction is the prime event in

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neurodegeneration, the clearance of impaired mitochondria is one of the main task for

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maintaining cell integrity in majority of neuropathologies. Along with it, inflammasome

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activation also plays a major role which is usually followed by mitochondrial

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dysfunction. The present review highlight basics of autophagy, mitophagy and

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inflammasome, the molecular mechanisms involved and more importantly it tries to

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elaborate the interplay between mitophagy and inflammasome in various neurological

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disorders. This will help in upgrading the reader’s understanding in exploring the link

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between mitophagy and inflammasome that has been dealt with limitations in past

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studies.

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Keywords: Cerebral ischemia, mitophagy, inflammasome, neurodegenerative

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disorder, neuroinflammation

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1. Introduction

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The genesis of neurological disorders and their symptoms are different but at the

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molecular level they have common attributes such as oxidative damage, aggregation

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of misfolded proteins, mitochondrial dysfunction, impairment of autophagy, and

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neuroinflammation1, 2. Impaired autophagy and neuroinflammation are the foremost

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events involved in several neurological disorders3, 4. Misfolded proteins, such as α-

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synuclein in Parkinson’s disease and amyloid β in Alzheimer’s disease, along with

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oxidative stress play central role in the progression of neurodegeneration1. This

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promotes activation of innate immune system to upregulate signaling of inflammasome

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complexes (NLRP3, NLRP1 and NLRC4) in the microglia for neuroinflammation.

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These mechanisms in some instances are also activated within the astrocytes and

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neurons that aggravates the disease5. In healthy cells, factors like nutrient deprivation,

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enhanced calcium influx and oxidative stress can lead to mitochondrial dysfunction6,

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7.

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known as mitophagy. This process of mitophagy gets dysregulated in neurological

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diseases8.

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neuroinflammation and mitophagy, hence keeping this in mind, the present review

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provides a brief overview of mitophagy and inflammasome, their mechanisms, and

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their associated cross talk in various neurological disorders.

Impaired mitochondria can be eliminated via specialized process of autophagy Recent

studies

report

that

there

is

a

connection

between

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2. Autophagy and Mitophagy

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Autophagy or self-eating is the process of degradation of impaired intracellular

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components which is mediated by autophagy related proteins (Atg) and lysosomes 9.

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Autophagy can be categorized into three types macroautophagy, microautophagy and

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chaperon-mediated autophagy

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comprises of five steps a) initiation of isolation membrane, b) elongation of isolation

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membrane, c) formation of autophagosome, d) fusion of autophagosome and

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lysosome and e) degradation of auto-phagolysosome 8. Autophagosome biogenesis

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is regulated by unc51 like autophagy acting kinase 1 (ULK1), autophagy related

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protein complex Atg16-Atg5-Atg12 and Atg 8 family proteins, while biogenesis and

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maturation of autophagosome is regulated by microtubule-associated protein 1 light

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chain 3 (LC3) and gamma-aminobutyric acid type 1 receptor (GABARAP). Soluble N-

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ethylmaleimide sensitive factor (NSF) attachment protein receptor (SNARE) proteins

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help in the fusion of autophagosome to lysosome and then the cargo is degraded by

10.

Mechanistically, the process of autophagy

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the lysosomal hydrolases

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well as cargo selective. Non-selective autophagy plays major role during nutrient

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deprivation in order to recycle essential nutrients from the cell, while cargo-selective

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autophagy accounts for the removal of damaged organelles and aggregation prone

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proteins that can be toxic for the cell 12. Cargo selective autophagy can be of various

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types depending on the target such as aggrephagy (aggregated proteins), mitophagy

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(mitochondria), ribophagy (ribosomes), peroxyphagy (peroxisomes), reticulophagy

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(endoplasmic reticulum) and xenophagy (pathogens).

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Selective autophagy of mitochondria is called mitophagy. It is a cellular quality control

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process to maintain mitochondria’s integrity and its functional state8. The mechanism

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of mitophagy was first identified in yeast and Uth1p gene was found to be an important

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regulator of mitophagy

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mitochondrial depolarisation favours sequestration of damaged mitochondria inside

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the autophagosome which is followed by its fusion with lysosome that ultimately leads

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to its degradation

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promotes the clearance of damaged mitochondria which is responsible for the

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generation of reactive oxygen species (ROS) as well as proapoptotic signals and

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depletion of ATP

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event associated with the development of pathology of several neurological ailments

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like Parkinson’s disease, cerebral ischemia, Alzheimer’s disease and Amyotrophic

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Lateral Sclerosis. Therefore, removal of damaged mitochondria is a prime requirement

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for halting progression of neuropathology. Figure 1 illustrates the molecular

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mechanisms behind mitophagy.

14.

15.

13.

Macroautophagy or autophagy can be non-selective as

Studies carried out in mammalian cells suggest that

Mitophagy plays central role in preventing cell death, as it

It is highly accepted that mitochondrial dysfunction is a major

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Figure 1: Illustration representing overview of molecular mechanisms behind

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mitophagy

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1) Mitochondrial depolarization followed by opening of mPTP caused by increased

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levels of ROS 2) Recruitment of PINK1 from the cytosol to OMM due to mitochondrial

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depolarization 3) Recruitment of Parkin to OMM induced by PINK1 4) Ubiquitination

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of adaptor proteins (OPTN, p62, SQSTM1 and TAXBP1) present on OMM induced by

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parkin 5) Tethering of ubiquitinated adaptor proteins with AMBRA1, a component of

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autophagosomal membrane via LIR-binding domain 6) Fusion of autophagosome and

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lysosome via interaction between HOPS and PLEKHM1 component of AP and Rab7

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which is a component of lysosome 7) Degradation of damaged or superfluous

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mitochondria via mitophagy.

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3 Molecular mechanisms of mitophagy

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3.1 Receptor mediated mitophagy

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A) Bnip3/Nix: Bnip3 (BCL2/adenovirus E1B 19 kDa interacting protein) and Nix

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(known as BNIP3L, a homolog of Bnip3) are pro-apoptotic mitochondrial proteins

18

where the former has Bcl-2 homology-3 domain (BH3) 16. The BH3 domain facilitates 8 ACS Paragon Plus Environment

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entry of Bnip3 to the outer mitochondrial membrane (OMM), which can be inhibited by

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phosphorylation at C-terminus due to diminished interaction between bnip3 and OPA1

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(a mitochondrial fusion regulator protein)17. Bnip3 regulates mitophagy during hypoxia

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while

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Bnip3/Nix is reported to be expressed in liver, kidney, brain, smooth muscles of

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healthy cells but it is not present ubiquitously

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many neurological disorders that modulates function of Bnip3/Nix

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conditions promote attachment of hypoxia-inducible factor 1 (HIF-1) to the promoter

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site of Bnip3/Nix, increasing expression of the same leading to mitophagy and thus

Nix regulates mitophagy during the development of erythroid lineage 19.

18.

Hypoxia is one of the key factors in

22,23.

20.

Hypoxic

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reduces levels of ROS and mitigates apoptosis21,

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Bnip3 also leads to enhanced mitophagy and thus cell death 24. Reports suggest that

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Bnip3 is upregulated significantly in a delayed manner following cerebral ischemia in

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neonatal stroke model, which is said to be responsible for cell death. It was observed

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that Bnip3 gene silencing was able to prevent neuronal cell death following cerebral

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ischemia 24.

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B) FUNDC1 (FUN14 domain-containing protein 1): FUNDC1 is a protein present on

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the OMM and is another important player of mitophagy

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components within its structure, a 3-transmembrane domain and a N-terminal

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cytosolic LIR-motif which binds with LC3 and GABARAP 25. It regulates autophagy via

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recruitment of LC3 to mitochondria and by regulating mitochondrial fusion and fission

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proteins, OPA1 and dynamin related protein 1 (DRP1) respectively 25, 26. Under normal

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conditions, FUNDC1 is inhibited by negative phosphorylation by Src kinase at tyr18

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and by casein kinase (CK2) at ser13 25,27. Hypoxic conditions or mitochondrial damage

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activates PGAM5, which in turn activates CK2 and thus promotes phosphorylation.

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LC3 then binds to damaged mitochondria, which then undergoes mitophagy

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Recently it was reported that activation of Bcl-xl inhibits PGAM5 which leads to

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inhibition of mitophagy28.

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C) Prohibitin 2 (PHB2): Although the role of OMM proteins has been characterized

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well during mitophagy, still extensive research is required to understand components

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of inner mitochondrial membrane (IMM) that are involved in mitophagy. Recently,

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PHB2 was characterized as a novel IMM protein and acts as a mitophagy receptor for

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Parkin-mediated mitophagy in mammalian cells

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rupture of OMM, that is achieved by PARK2 mediated ubiquitination and degradation

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of OMM proteins followed by expression of PHB2 on OMM which further facilitates

29.

But excessive activation of

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It has two important

27.

Mitochondrial damage leads to

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binding of LC3 leading to mitophagy

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achieved by USP14 inhibition. Results from co-immunoprecipitation assay showed

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that interaction of PHB2 with LC3 depends on the activity of PARK2

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it has been found that PHB2 does not interact with the GABA-type A receptor-

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associated protein (GABARAP) and GABARAP-L2. As ubiquitin proteasome system

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(UPS) is impaired in several neurodegenerative disorders, UPS may be targeted for

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therapeutic purposes. Many de-ubiquitinating (DUB) enzymes are being explored.

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USP14 is one of the DUB enzymes which regulates UPS negatively

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supports that inhibition of USP14 leads to enhanced mitochondrial clearance. It also

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Mitochondrial membrane rupture can be 31.

Interestingly,

32.

Studies

induces OMM rupture followed by interaction of PHB2-LC3 leading to mitophagy 30.

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3.2 Parkin-PINK dependent mitophagy

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PINK1 is PTEN-induced putative kinase which belongs to a family of Ser/Thr kinase

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and thereby having kinase activity along with mitochondrial target sequence and it also

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acts as a sensor for detection of polarized state of mitochondria 33, 34. While Parkin is

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a E3-Ubiquitin ligase, PINK1 acts as an upstream regulator of PARKIN. This is

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supported by a study in which it was found that PINK1-KO phenotype was rescued

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with the overexpression of PARKIN but overexpression of PINK1 was not able to

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rescue the PARKIN-KO phenotype in drosophila

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mitochondria having proteins containing mitochondrial target sequence (MTS) and

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single membrane spanning domain (SMSD) get entry into IMM through the

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translocase of outer mitochondrial membrane (TOM) and translocase of inner

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mitochondrial membrane (TIM) complex. Studies have reported two forms of PINK1,

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a 64-kDa Full length PINK1 and a 52-kDa PINK137. Under normal conditions, the

25

former is present predominantly that enters the IMM by cleavage of MTS and is

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converted into 60-kDa form. This is further cleaved by PARL (Presenilin associated

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Rhomboid like protein) leading to formation of a 52-kDa form which is rapidly

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processed and degraded by proteases and thus maintains the levels of PINK1 low and

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inhibits mitophagy in healthy mitochondria 37, 38.

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Under pathological conditions, mitochondria undergoes depolarization. To mimic the

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same physiological conditions, studies have been carried out by using Carbonyl

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cyanide m-chlorophenyl hydrazone (CCCP), which is a mitochondrial uncoupler39.

33

CCCP drastically reduces mitochondrial membrane potential (MMP), which blocks

34

transport of PINK1 to IMM and thus PINK1 will not be processed by PARL leading to

35, 36.

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In healthy cells, polarized

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accumulation of the 60-kDa form of PINK1 followed by recruitment of PARKIN37, 40.

2

This recruitment of PARKIN facilitates ubiquitination of OMM adaptor proteins like p62,

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optineurin, SQSTM1, NBR1, TAXBP1 and this ubiquitination solely depends on the

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TBK1 a Ser/Thrkinase that promotes phosphorylation of RAB7A, an activator of

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mitophagy33,

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autophagosome through their LIR motif (LC3-interacting region) to induce mitophagy

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and promotes biogenesis of autophagosome via binding with AMBRA1 (an autophagy

8

promoting protein), followed by fusion of autophagosome with the lysosome via

9

autophagosomal proteins PLEKHM1 and HOPS and lysosomal protein-Rab7 and

39, 41.

These adaptor proteins followed by ubiquitination

42, 43.

targets

10

promotes mitophagy

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was found to promote mitophagy independent of PINK1/PARKIN, via activation of

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IKKα which in turn phosphorylates AMBRA, an activator of mitophagy

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studies have suggested the role of PARKIN in apoptosis, as Parkin inhibits BAK, a

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pro-apoptotic factor and thereby inhibits apoptosis and promotes clearance of

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damaged mitochondria. Along with this it also promotes clearance of apoptotic

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mitochondria and restricts their potential pro-inflammatory effect 44.

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Mitochondrial outer membrane Rho GTPases Miro1/2 (Miro) are the adaptor proteins

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that anchors mitochondria to motor proteins, which results in mitochondrial arrest

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facilitating mitophagy. In healthy cells, Miro interacts with Parkin independent of

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PINK1. However damaged mitochondria disrupt pool of Miro-Parkin due to

21

overexpression of PINK1 leading to ubiquitination and degradation of Miro and thus

22

impairs mitophagy

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homolog-long (PTEN-L) prevents PINK1/PARKIN mediated mitophagy by preventing

24

translocation of Parkin as well as promotes phosphorylation of ubiquitin 45.

44.

Recently a novel ligase, identified as HUWE1 E3 ligase, 43.

Recent

Recently it was been identified that phosphatase and tensin

25 26

3. Inflammasomes

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Inflammasomes are cytosolic complexes composed of three chief components:

28

sensor-NLRs, adaptor-ASC, effectors-pro-caspase1

29

types: canonical and non-canonical which activates caspase-1 and caspase-4,5,11

30

respectively 48-50. Innate immune response is the first line of immune defence against

31

invading pathogens and endogenous danger signals by pattern recognition receptors

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(PRRs) through sensing the pathogen- and danger- associated molecular patterns

33

(PAMPs and DAMPs) 51, 52. Dendritic cells, microglia, astrocytes, neutrophils, epithelial

34

cells, macrophages and monocytes express huge amount of PRRs. PRRs are of

46, 47.

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Inflammasomes are of two

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various types including members of Toll-like receptors (TLRs), C-type lectins (CTLs),

2

nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) or absent in

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melanoma 2 (AIM2)-like receptors (ALRs). TLRs are present on the extracellular

4

membranes, while NLRs are present in the cytosol. NLRs are mainly responsible for

5

formation of inflammasomes

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NODs (NOD1, 2, NOD3/NLRC3, NOD4/NLRC5, NOD5/NLRX1, CIITA), NLRPs

7

(NLRP1–14,also called the NALPs) and ICE protein-activating factor (IPAF; NLRC4

8

and NAIP) 5. NLRs consists of a tripartite structure including C-terminal leucine-rich

9

repeats (LRRs) domain, NACHT or NOD (nucleotide-binding-oligomerization domain)

10

an intermediate domain and N-terminal effector domain can be pyrin domain (PYD) or

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caspase recruitment domain (CARD)54. After sensing a stimuli, NLR undergoes

12

oligomerization by the interaction between their NACHT domains, then the

13

oligomerized NLR interacts with ASC through its PYD domain, followed by recruitment

14

of procaspase-1 by ASC via interaction of CARD/CARD. This is followed by cleavage

15

and activation of pro-caspase-1 to caspase-1, which further stimulates the maturation

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of pro-inflammatory cytokines pro-interleukin 1β (IL-1β) and pro-IL-18 to active IL-1β

17

and IL-18

18

Gasdermin-D leading to pyroptosis and release of cytokines 56, 57. Indeed activation of

19

inflammasome is very essential in host-defence mechanism, although excessive

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activation can damage the host cells. Recent study suggests that this excessive

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inhibition is kept in check by Cullin1 (CUL1) component of the Skp1-Cullin1-F-box E3

22

ligase which binds with NRPL3 and promotes ubiquitination, not to degrade the protein

23

but to prevent activation of inflammasome

24

mitochondrial

25

inflammatory cytokines can also trigger mitochondrial damage60. So, it is quite

26

ambiguous that what comes first.

55.

53.

There are three subfamilies within the NLR family-

This is followed by maturation of cytokines and promotes cleavage of

damage

promote

activation

58.

of

Several studies suggest that inflammasomes59.

However,

27 28 29

4. Interplay between mitophagy and inflammasomes in neurological diseases A) Cerebral Ischemia

30

Activation of inflammasome is one of the events involved in cerebral ischemia5, 61. First

31

evidence of involvement of NLRP1 inflammasome in cerebral ischemia was reported

32

by Abulafia et al

33

receptor pyrin domain-containing 3 (NLRP3) inflammasome is reported to be

34

associated in cerebral ischemia. Apart from this, NLRP1, NLRC4, AIM2 are also

62.

The nucleotide binding domain leucine-rich repeat-containing

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involved in the inflammatory cascade in cerebral ischemia5. In cerebral ischemia levels

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of ROS are elevated leading to NLRP3 inflammasome activation, which results in

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release of IL-1β and IL-18 causing neuroinflammation3, 5, 63. NLRP1 is reported to be

4

activated in response to acid sensing ion channel (ASIC) activation, which further

5

release IL-1β and IL-18 and aggravate neuroinflammation 5. ATP depletion also

6

stimulates the activation of NLRP1 inflammasome via AMP-activated protein kinase

7

(AMPK). Nuclear factor kappa B (NFκB) and mitogen-activated factor (MAPK) lowers

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the expression and activation of NLRP1 and NLRP3 inflammasomes under ischemic

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condition 64.

10

NLRP3, NLRP1, NLRC4 and AIM2 inflammasomes are expressed and activated in

11

microglia and exacerbate the ischemic condition

12

inflammasome complex regulates the inflammatory response, apoptotic and pyroptotic

13

death of microglial cells under ischemic condition

14

suppresses the activation of inflammasomes post ischemia

15

nicotine worsens cerebral ischemic condition by stimulating the inflammasome

16

activation via inhibition of ER-β signaling in post ischemic brain

17

that nuclear factor erythroid 2-related factor 2 (Nrf2) inhibits the activation of NLRP3

18

inflammasome by regulating the thioredoxin 1 (Trx1)/ thioredoxin interacting protein

19

(TXNIP) complex in the model of cerebral ischemia. It is suggested that under

20

oxidative stress conditions, Trx1/TXNIP complex dissociates and release TXNIP

21

which further stimulates the activation of NLRP3 inflammasome and Nrf2 acts as an

22

antioxidant agent which plays a protective role in the animal model of cerebral

23

ischemia 67.

24

Cerebral ischemia involves depletion in ATP and increase in AMP due to mitochondrial

25

dysfunction leading to

26

mitochondrial fission factor (MFF) which activates DRP1 and thus stimulates

27

mitochondrial fission and mitophagy

28

during reticulocyte maturation and in cerebral ischemia reperfusion-induced

29

mitophagy 69, 70. Acidic post-conditioning (APC) is a condition in which CO2 is inhaled

30

during reperfusion after cerebral ischemia leading to mild acidosis. It is reported that

31

APC maintains the mitochondrial membrane potential

32

sensor present in the mitochondria of neuronal cells which reduces the mitochondrial

33

membrane potential following oxidative stress 72. Findings suggest that APC alleviates

34

cerebral I/R injury via activation of mitophagy by recruiting PARK2 in mitochondria in

65.

65.

In addition to this, NLRC4 Estrogen receptor β (ER-β) 66.

66.

It is reported that It is also reported

activation of AMPK, promoting phosphorylation of 7, 68.

BNIP3L is mainly involved in mitophagy

13 ACS Paragon Plus Environment

71.

ASIC1 is a main proton

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73.

Page 14 of 40

Peroxynitrite (ONOO-) is the main marker of

1

a mouse model of cerebral ischemia

2

reactive nitrogen species which promotes nitration of proteins. This further activates

3

mitochondrial fission and thus activates mitophagy

4

group A member 1 (NR4A1) is involved in regulating mitochondrial function. It is

5

reported that NR4A1 exacerbates the cerebral I/R injury by reducing the expression

6

of Mfn2 through MAPK-ERK-CREB signaling pathway

7

reperfusion injury the PINK1/Parkin/p62 pathway is activated to induce mitophagy

8

(Figure 2).

74.

Nuclear receptor subfamily 4

75.

In cerebral ischemia/ 76

9 10

Figure

2:

Illustration

representing

interplay

11

inflammasome in cerebral ischemia: Process of cerebral ischemia involves multiple

12

signalling pathways that activate or inhibit mitophagy (1-6) and inflammasome (7). 1)

13

Hypoxia occurring during cerebral ischemia increase levels of Bnip3/Nix via activation

14

of HIF-1, followed by activation of Beclin-1 which ultimately induces mitophagy 2)

15

Reperfusion injury following cerebral ischemia can produce ROS which also activates

16

mitophagy via PINK1/Parkin activation. 3) Decreased levels of ATP and increased

17

levels of AMP following mitochondrial dysfunction activates AMPK followed by fission 14 ACS Paragon Plus Environment

between

mitophagy

and

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1

of mitochondria due to activation of MFF and Drp1, a mitochondrial fission protein and

2

thus promotes mitophagy 4) Mitochondrial fission is also promoted by nitration of

3

proteins due to generation of RNS which activates mitophagy 5) Mitophagy is also

4

promoted by increased levels of LC3II, p62 and Beclin1 6) Acidic post-conditioning

5

(APC) activates PARK2 during ischemic condition and thus facilitates mitophagy 7)

6

Increased levels of ROS and activation of AMPK activates NLRP3 and NLRP1

7

respectively, which in turn activates Il-1β, IL-18 via activation of caspase-1 and

8

promotes neuroinflammation.

9

B) Parkinson’s disease (PD)

10 11

Oxidative stress and activation of both microglial cells and inflammasomes play a key

12

role in the pathology of PD as they promote neuroinflammation and neurodegeneration

13

77

14

which in turn activates c-Abl kinase which facilitates activation of NLRP3

15

inflammasomes

16

microglial cells which can also activate inflammasomes 79. Neurotoxins like rotenone,

17

MPTP, paraquat, dieldrin, manganese, salolinon, etc. increase levels of H2O2 which

18

activates JNK MAPK and subsequently activate caspase-1 and 3 leading to cell death

19

and promotes induction of PD

20

of α-synuclein via activation of inflammasome 81.

21

Crosstalk between caspase-1 and NLRP3 have been suggested by studies which

22

support that α-synuclein promotes activation of TLR2 which facilitates formation of

23

NLRP3 assembly and ultimately promotes synthesis of IL-1ß

24

levels of IL-1ß promotes generation of ROS and also promotes release of cathepsin-

25

B which finally upregulates NLRP3

26

synuclein also promotes activation of TLR4/NF-kB and NLRP3/caspase-1 signaling

27

mechanism in adult neural stem cells (ANSCs), which was confirmed by knockdown

28

of either caspase-1 or NLRP3 which inhibited proliferation of ANSCs

29

reported that miRNA-7 activates neurogenesis in subventricular zone (SVZ) via

30

inhibition of NLRP3/caspase-1 signalling mechanism in ANSCs 84.

31

Recently, researchers found that there was increased levels of NLRP3 within

32

mesencephalic neurons of PD patients

33

inflammation and death of dopaminergic neurons in which they have shown that

34

inhibition of hepatic inflammasomes by siNLRP3 (silencing RNA) leads to decreased

(Figure 3). More specifically, generation of ROS leads to increased oxidative stress 78.

ROS

also increases the activity of cathepsin-B in activated

80.

Activation of caspase-1 also promotes aggregation

79, 83.

82,83.

The increased

Furthermore, it has been reported that α-

85.

84.

It is also

Studies have described the role of liver

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Page 16 of 40

1

spreading of inflammatory cytokines to brain and thus halts the progression of

2

neuroinflammation and also the degeneration of dopaminergic neurons

3

Mitochondrial serine protease HtrA2 inhibits activation of NLRP3 and AIM2

4

inflammasomes which was confirmed by disruption of HtrA2 activity leading to

5

upregulation in NLRP3 and AIM2 inflammasomes in macrophages

6

demonstrated that MPTP promotes impairment in autophagy via induction of

7

PI3K/Akt/mTOR pathway which was confirmed by assessing levels of Beclin-1 and

8

LC3. Levels of which was found to be decreased 88. Many PPAR ß/delta agonists are

9

reported to have anti-inflammatory properties but mechanisms are yet to be explored

87.

86.

It has been

10

89.

11

agonist and it was found that it protected dopaminergic neurons in the midbrain,

12

increased levels of dopamine in the striatum and also inhibited activation of NLRP3

13

inflammasomes in astrocytes in a MPTP-mouse model of PD 89.

14

ß-arrestin-2 mediated dopamine D2-receptor (Drd2) signaling mechanism is

15

considered as potential anti-inflammatory target. In one study they used Drd2 agonist

16

and they found that it suppressed activation of NLRP3 inflammasome and also

17

decreased levels of caspase-1 and IL-1ß in MPTP-induced mouse model

18

and PARKIN are the widely-studied protein related to PD. PINK1-PARKIN pathway is

19

considered as most important pathway related to mitophagy

20

of mitochondria, mitochondrial rhomboid protease (PRAL) instead of PGAM5,

21

(phosphoglycerate mutase which promotes mitochondrial division by phosphorylation

22

of Drp1) cleaves PINK1 which leads to accumulation of PINK1 in the OMM

92.

23

Deficiency of PGAM5 leads to development of PD-like movement disorder

93.

24

Functions of PGAM5 are regulated by Syntaxin 17 which is a novel mitochondrial

25

protein mediating normal division of mitochondria under healthy conditions but upon

26

stimulation of mitophagy, syntaxin 17 detaches from Drp1 and binds with Atg14L

27

promoting formation of autophagosomes and also promotes elongation of

28

mitochondria. Upon mitophagy, cleaved PGAM5 promotes dephosphorylation of

29

FUNDC1 which promotes excessive breakdown of mitochondria

30

fusion is mediated by mitofusins and Opa1, while fission is mediated by Drp1

31

Mitochondrial fusion and fission are important for maintaining mitochondrial

32

homeostasis which is mediated by PINK1 and PARKIN, which was confirmed by one

33

study in which it was found that mitofusin (Mfn) is the mitochondrial fusion protein

34

which is ubiquitinated by PINK1 and PARKIN. Knockdown of Mfn1 and Mfn2 results

In a study researchers used GW501516, a selective and high-affinity PPAR ß/delta

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91.

90.

PINK1

Upon depolarization

94.

Mitochondrial 95, 96.

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ACS Chemical Neuroscience

1

in altered MMP and inhibits recruitment of Parkin on OMM 97. Recently, it was identified

2

that retro-translocation of Mfn2 promotes detachment of mitochondria from ER

3

thereby, accelerates mitophagy

4

extract (GSE) preserves mitochondrial function, improved function of flight muscle,

5

prolonged life span via activation of mitophagy in PINK1 mutant drosophila model of

6

PD 99. Rotenone , a neurotoxin , used to develop model of PD induces autophagy and

7

mitophagy in PC12 cells100. Rotenone inhibits mitochondrial biogenesis and reduces

8

the mitochondrial membrane potential. PINK1 inhibits mitochondrial biogenesis by

9

inhibiting PGC1-α, which in turn inhibits PINK1/PARKIN protein and ultimately inhibits

10

mitophagy. Which indicates that mutual antagonism exists between PINK1/PARKIN

11

and PGC1-α.This maintains mitochondrial homeostasis in rotenone-induced

12

neurotoxicity 101.

98.

More recently, it was discovered that grape skin

13 14

Figure

3:

Illustration

15

inflammasome in Parkinson’s disease: Mitochondrial dysfunction in PD arises as a

16

result of exposure to neurotoxins. A) Increased ROS due to mitochondrial dysfunction

17

activates c-Abl and cathepsin B which further activates NLRP3 inflammasome. This

18

then

activates

Il-1β

representing

via

activation

interplay

of

between

caspase-1/3

17 ACS Paragon Plus Environment

and

mitophagy

finally

and

promotes

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1

neuroinflammation B) Increased levels of ROS as well as activation of caspase-1/3

2

induces the misfolding of wild-type α-synuclein to toxic α-synuclein which promotes

3

extensive degradation of mitochondria, promotes cleavage of PGAM5 instead of

4

PINK1 via activation of PARL. Further the cleaved PGAM5 dephosphorylates

5

FUNDC1 resulting into extensive mitochondrial breakdown C) Exposure to

6

neurotoxins also generates H2O2 which activates Jnk-MAPK pathway promoting

7

neuroinflammation via activation of caspase-1/3.

8

C) Alzheimer ’s disease

9

Inflammation plays a major role in the pathogenesis of AD, which is supported by

10

studies indicating enhanced levels of inflammatory cytokines in the brain sample of

11

AD patients

12

pathogenesis of AD, as a study found that NLRP3 enhances accumulation of Aβ

13

protein

14

overload of neuritic plaque in transgenic mice model of AD 104. Priming of microglia by

15

β-amyloid pathology resulted in activation of IL-1β leading to significant cognitive

16

decline as compared with wild type LPS-treated mice. But it was reported that priming

17

of microglia does not activate IL-1β or NFκB p65 nuclear translocation. But upon

18

secondary stimulation, it activates the IL-1β and also p62 nuclear translocation, from

19

this it was confirmed that secondary inflammatory insults induces cognitive

20

impairments specifically in in-vivo models 105.

21

Glial maturation factor (GMF) is a pro-inflammatory protein which activates glial cells

22

to stimulate neuroinflammation and neurodegeneration in AD. GMF is mainly present

23

and expressed in proximity to Aβ and tau in the temporal cortex of human AD brain.

24

Upon prolonged accumulation and aggregation of Aβ peptide, glial cells are activated

25

and secrete pro inflammatory cytokines. GMF enhances the activation of NLRP3

26

inflammasome and promotes neuroinflammation in AD 106. Although the link between

27

inflammasome and mitophagy in AD is yet not clearly understood, a link may be

28

supported by the study which suggests that mitophagy is impaired in AD resulting in

29

increased oxidative stress and deficiency of cellular energy triggering the

30

accumulation of Aβ peptide and tau protein, which further impairs mitophagy and

31

activates NLRP3 inflammasome

32

potential (MMP) due to which recruitment of PINK1/Parkin in the outer membrane of

33

dysfunctional mitochondria is halted 108. Accumulation of tau protein impairs mitophagy

34

by inhibiting the recruitment of Parkin in dysfunctional mitochondria by sequestering it

103.

102.

NLRP3 inflammasome was also found to be important in the

It is also reported that absence of NLRP3 inflammasome reduces the

107.

Tau protein increases mitochondrial membrane

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ACS Chemical Neuroscience

109.

1

in cytosol

Post-translational modifications (PTMs) in the tau protein leads to

2

impairment of mitophagy and this idea came after a study which suggests that NH2-

3

truncated tau protein promotes aberrant recruitment of Parkin and UCHL-1 modulator

4

of mitophagy which promotes deregulation of mitophagy 110. Aging is a natural process

5

which is associated with inflammation. This process is known as inflammaging. This

6

is mediated by inflammasome activation and is associated with the development of

7

deleterious conditions in the aging brain such as Alzheimer’s disease 111.

8 9

Fig 4: Illustration representing interplay between mitophagy and inflammasome

10

in Alzheimer’s disease: Mitochondrial dysfunction is the main pathological event

11

during AD which leads to accumulation of damaged mitochondria, which in turn

12

triggers production of ROS promoting accumulation of Aβ and Tau-proteins A) This in

13

turn activates microglia via release of glial maturation factor (GMF), followed by

14

activation of NLRP3-inflammasome which further promotes neuroinflammation. B)

15

Accumulation of Aβ and Tau-protein also impairs mitophagy by inhibiting recruitment

16

of PINK1/Parkin via two ways: either by increasing MMP or by directly promoting

17

sequestration of PINK1/Parkin in the cytosol.

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Page 20 of 40

D) Amyotrophic Lateral Sclerosis

1 2

Amyotrophic lateral sclerosis (ALS) is a motor neurodegenerative disease involving

3

degeneration of both upper and lower motor neurons leading to motor and extra-motor

4

symptoms 112,113. Mitochondrial dysfunction and autophagy plays an important role in

5

ALS 114. Optineurin is an autophagy receptor that is recruited to the ubiquitinated OMM

6

proteins via its ubiquitin binding domain. On the other side it consists of light chain 3

7

(LC3) binding domain (LIR) which binds to LC3 for autophagosome formation favoured

8

by assistance of parkin 41. Optineurin momentarily binds to dysfunctional mitochondria

9

and allows the recruitment of double FYVE-containing protein 1 (DFCP1) for the

10

initiation of autophagosome formation and microtubule-associated protein LC3

11

recruitment 41.

12

In ALS there is mutation of optineurin E478G, as a result of which mitophagy is

13

subdued which exacerbates the pathology 41. Along with optineurin, ALS also involves

14

mutation of TANK-binding kinase 1 (TBK1) which phosphorylates optineurin in its

15

serine 177 residue and stimulates its binding to Atg8/LC3 and autophagic clearance

16

115.

17

required for binding of ubiquitin to LC3, which binds to LC3 via its LIR region. Studies

18

suggest that ALS-associated mutation in LIR region i.e. D337E, L341V reduces the

19

ability of binding of SQSTM1/p62 to LC3

20

containing protein (VCP) in the damaged outer mitochondrial membrane depends on

21

Parkin-mediated ubiquitination of damaged mitochondria 117. VCP undergoes mutation

22

during ALS, which leads to impairment of mitophagy 118.

23

Fibroblasts of ALS patients express C9orf72, which assists in protein synthesis,

24

undergoes mutation. This interacts with ULK1 and initiates autophagy

25

between inflammation and ALS was first established by Troost et. al., where they

26

found that brain of sporadic ALS patients expressed higher levels of MHC (major

27

histocompatibility complex) and HLA (human leucocyte antigens), which are important

28

components of inflammation

29

inflammation which were found to be activated in ALS-linked mutant SOD1 mice

30

Apart from these, reactive oxygen and nitrogen species were also found to be

31

upregulated. These reactive nitrogen are then converted into peroxynitrite leading to

32

protein nitration, which triggers the activation of caspase-1/inflammasome

33

involves accumulation of mutant superoxide dismutase 1 (SOD1)

34

sensed by ASC component of inflammasome as a result of which there is activation

Sequestosome 1 (SQSTM1) encodes for SQSTM1/p62 which is an adaptor protein

120.

116

(Figure 5). Localization of valosin-

119.

The link

NFкB and TLRs are important component of

20 ACS Paragon Plus Environment

123,

122.

121.

ALS

which can be

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ACS Chemical Neuroscience

124.

1

of caspase-1 and IL-1β in microglia which leads to neuroinflammation

Levels of

2

NLRP3 and other inflammasome components i.e. ASC, caspase-1, IL-1β and IL-18

3

were found to be overexpressed in the spinal cord of ALS-linked mutant SOD1 (G93A)

4

mice astrocytes and also in the tissue of ALS patient these levels are increased as

5

compared to healthy volunteers 125.

6 7

Figure 5: Illustration representing the role of genetic alteration and inflammatory

8

cascade in the development of ALS: A) Genetic alteration: 1) Mutations in TBK1

9

promotes phosphorylation of ubiquitinated adaptor proteins 2) E4784 mutation impairs

10

tethering of ubiquitinated adaptor proteins and AMBRA1 of AP and ultimately impairs

11

mitophagy 3) D337E and L341V mutation impairs autophagy via inhibiting interaction

12

of SQSTM1 and AMBRA1 of AP B) Inflammatory cascade: development of ALS

13

activates inflammasome directly via activation of 1) TLRs and NFkB 2) SOD1 or

14

indirectly via activation of 3) ROS and RNS which promotes nitration of protein.

15

Activation of inflammasome further activates caspase-1 followed by activation of Il-1β,

16

IL-18 and further triggers neuroinflammation.

17 18

E) Other neurological disorders 21 ACS Paragon Plus Environment

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Page 22 of 40

1 2

Other neurological conditions have also shown the involvement of mitophagy and

3

inflammasomes. These include epilepsy, Huntington’s disease, multiple sclerosis and

4

autism. Details of each have been summarised in table 1.

5

1. Huntington’s disease (HD)

6

Huntington’s disease is associated with the mutation of huntingtin gene (mtHtt) which

7

activates a cascade of detrimental events resulting in neurodegeneration.

8

Mitochondrial dysfunction is one of the major events involved in HD. VCP translocates

9

to mitochondria and interacts with UBXD1 leading to degradation of the OMM protein

10

MCL1, as a result of which mitophagy increases126,

11

mediated mitophagy128. Huntingtin facilitates the association of p62 with integral

12

autophagosome component, however due to mutation in huntingtin, mitophagy is

13

impaired129. mtHtt also triggers the activation of inflammasomes via NFkβ. This further

14

activates neuroinflammation by upregulating IL-6, IL-8 and TNF-α130. mtHtt inhibits the

15

phosphorylation induced by IGF-1/Akt, leading to neurotoxicity131, 132.

16

127

. mtHtt disturbs PINK/Parkin

2. Epilepsy

17

In case of refractory temporal lobe epilepsy with hippocampal sclerosis, LC3B was

18

found to be upregulated133. Evidence of role of inflammasome in epilepsy has been

19

reported in many studies suggesting that deficiency of COX and its product PGF-2α

20

may be responsible for increased susceptibility towards epilepsy134. Overexpression of

21

genes related to pro-inflammatory cytokines and NOS have been found in the

22

olfactory-bulb of frontal lobe epilepsy patients135. Epilepsy enhances release of HMGB-

23

1, an inflammatory cytokine which promotes neuroinflammation via activation of TLR-

24

4136.

25

3. Multiple sclerosis (MS)

26

Involvement of mitophagy and inflammasome have been documented in MS patients.

27

Increased levels of ATG5 and parkin have been reported in body fluids of MS

28

patients137. Active involvement of caspase 1 has also been reported in MS which

29

directly leads to inflammation138 139.

30

4. Autism

31

Wdfy3 is an autism risk gene ideally required for maintaining mitochondrial

32

homeostasis. Mutation of this gene in autism leads to inhibition of mitophagy 140. AIM2

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ACS Chemical Neuroscience

1

and NLRP3 have been found to be upregulated in the patients of autism, suggesting

2

the involvement of inflammasomes in autism141.

3 4 5

Table1: List of neurological diseases involving molecular mechanisms behind

6

mitophagy and inflammasome

7 Sr.No.

Neurological disease

Event

Target

Molecular mechanism

GAPDH

Abnormal interaction of polyglutamine repeats with the GAPDH prevents GAPDHmediated mitophagy

VCP

Mitophagy PINK1/Parkin

1

Huntington’s disease

Inflammasome

Presence of mtHtt facilitates interaction of VCP and UBXD1 results into degradation of OMM-protein MCL1 leads to uncontrolled mitophagy mtHtt impairs PINK1/Parkin-mediated mitophagy

C-terminal of Htt

Impaired p62-mediated mitophagy due to mutation in C-terminal of Htt

NFkB

mtHtt activates NFkB cascade and upregulates IL-6,IL-8,TNF-α and promotes neuroinflammation

CCL4 and MMP9

Upregulated in the brains of HD patients

IGF-1/Akt

mtHtt mediates neurotoxicity via inhibitory effect on phosphorylation induced by IGF-1/Akt

23 ACS Paragon Plus Environment

Reference

142

126, 127

128

129

130

143

131, 132

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LC3B Mitophagy

PGF-2α

Epilepsy Inflammasome

2

Mitophagy

3

Page 24 of 40

LC3B upregulated in case of rTLE with hippocampal sclerosis Lack of PGF-2α increased susceptibility to the seizures in immature brain

Proinflammatory cytokines and NOS genes

Upregulated in olfactory bulbs of FLE patients

HMGB-1

Epilepsy promotes release of HMGB-1, an inflammatory cytokine, activates TLR-4 leads to neuroinflammation

ATG5 and Parkin

ATG5 and Parkin activates mitophagy

Caspase-1

Caspase-1 activation followed by activation of glial inflammasomes and pyroptosis in MS

Multiple sclerosis

133

134

135

136

137

138

Inflammasome

Mitophagy

4

Autism Inflammasome

ASC and Caspase-1

MS promotes activation of inflammasome via activation of ASC and caspase-1

Wdfy3

Mutation in Wdfy3 leads to inhibition of mitophagy

AIM2 and NLRP3

Upregulated in case of ASD patients, responsible for inflammasome activation

I-FABP

Compromised GI permeability promotes release of I-FABP followed by release of ATP, an activator of DAMP and activates inflammasome

139

140

141

141

1 2

5. Concluding Remarks

3

Mitophagy and inflammasome activation are two main cellular events involved in

4

several neurological diseases. The former is important for elimination of damaged 24 ACS Paragon Plus Environment

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ACS Chemical Neuroscience

1

mitochondria while the later provides a molecular platform for activation of caspase-1

2

which secretes IL-1β in response to various insults leading to neuroinflammation in

3

various neurological diseases. Each and every neurological disease comes with its

4

unique pathogenesis. Although, mitophagy and inflammasome have been implicated

5

in various neurological diseases like AD, PD, HD, MS, etc. The interplay between the

6

two in various neurological disorders is yet not clear. Thus, here we have tried to find

7

the link between inflammasome and mitophagy in different neurological diseases that

8

was not put forward effectively. By developing some novel therapeutics against the

9

target which regulates mitophagy and inflammasome activation, one may pave a way

10

to halt the progression of neurological disorders.

11

6.

12

Authors acknowledge Department of Science and Technology (DST),Govt.of India for

13

their financial support through a grant (SB/YS/LS-196/2014), International Society for

14

Neurochemistry (ISN) Return Home grant, Department of Pharmaceuticals, Ministry

15

of Chemical and Fertilizers, Govt of India and National Institute of Pharmaceutical

16

Education and Research (NIPER) Ahmedabad, Gandhinagar, India.

17

Acknowledgements

7. Conflict of Interest

18

The authors declare that they have no conflicts of interest.

19

Authors Contributions:

20

RK, DS, PB, KD and DY conceived and designed the study. RK,DS,PB,

21

KD,AB,HK,LM,GV,VP,VK, KK and DY outlined the performed rigorous literature

22

search. RK, DS, PB, KD, KK, DY conceived and designed the figures and images. RK,

23

DS, PB, KD, KK, and DY wrote the manuscript.

24

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Inflammasome

Mitophagy

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Cerebral Ischemia Multiple Sclerosis Parkinson’s Disease Alzheimer’s Disease Amyotrophic Lateral Sclerosis Autism Epilepsy Huntington’s Disease

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