Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2018 Jan 17

PMID 29337137

Citations 281

Authors

Thomas G McWilliams

Alan R Prescott

Lambert Montava-Garriga

Graeme Ball

Francois Singh

Erica Barini

Miratul M K Muqit

Simon P Brooks

Ian G Ganley

Affiliations

Soon will be listed here.

Abstract

Dysregulated mitophagy has been linked to Parkinson's disease (PD) due to the role of PTEN-induced kinase 1 (PINK1) in mediating depolarization-induced mitophagy in vitro. Elegant mouse reporters have revealed the pervasive nature of basal mitophagy in vivo, yet the role of PINK1 and tissue metabolic context remains unknown. Using mito-QC, we investigated the contribution of PINK1 to mitophagy in metabolically active tissues. We observed a high degree of mitophagy in neural cells, including PD-relevant mesencephalic dopaminergic neurons and microglia. In all tissues apart from pancreatic islets, loss of Pink1 did not influence basal mitophagy, despite disrupting depolarization-induced Parkin activation. Our findings provide the first in vivo evidence that PINK1 is detectable at basal levels and that basal mammalian mitophagy occurs independently of PINK1. This suggests multiple, yet-to-be-discovered pathways orchestrating mammalian mitochondrial integrity in a context-dependent fashion, and this has profound implications for our molecular understanding of vertebrate mitophagy.

Citing Articles

PPTC7 acts as an essential co-factor of the SCF ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.

Xu X, Chen Y, Fei S, Jiang X, Zhou X, Xue Y Cell Death Dis. 2025; 16(1):145.

PMID: 40025034 PMC: 11873123. DOI: 10.1038/s41419-025-07463-w.

Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.

Sinclair L, Youdale T, Spinelli L, Gakovic M, Langlands A, Pathak S Nat Immunol. 2025; 26(3):429-443.

PMID: 40016525 PMC: 11876071. DOI: 10.1038/s41590-025-02090-1.

Alterations of PINK1-PRKN signaling in mice during normal aging.

Baninameh Z, Watzlawik J, Hou X, Richardson T, Kurchaba N, Yan T Autophagy Rep. 2025; 3(1).

PMID: 40008113 PMC: 11855339. DOI: 10.1080/27694127.2024.2434379.

Canonical and noncanonical autophagy: involvement in Parkinson's disease.

Sakurai M, Kuwahara T Front Cell Dev Biol. 2025; 13:1518991.

PMID: 39949604 PMC: 11821624. DOI: 10.3389/fcell.2025.1518991.

Impaired Mitochondrial Function and Ubiquitin Proteasome System Activate α-Synuclein Aggregation in Zinc-Induced Neurotoxicity: Effect of Antioxidants.

Singh G, Mittra N, Singh C J Mol Neurosci. 2025; 75(1):16.

PMID: 39907853 DOI: 10.1007/s12031-024-02293-5.

References

Rojansky R, Cha M, Chan D . Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. Elife. 2016; 5. PMC: 5127638. DOI: 10.7554/eLife.17896. View

Nishino H, Shimano Y, Kumazaki M, Sakurai T . Chronically administered 3-nitropropionic acid induces striatal lesions attributed to dysfunction of the blood-brain barrier. Neurosci Lett. 1995; 186(2-3):161-4. DOI: 10.1016/0304-3940(95)11311-j. View

Zlokovic B . Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011; 12(12):723-38. PMC: 4036520. DOI: 10.1038/nrn3114. View

Perry V, Holmes C . Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014; 10(4):217-24. DOI: 10.1038/nrneurol.2014.38. View

Gong G, Song M, Csordas G, Kelly D, Matkovich S, Dorn 2nd G . Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science. 2016; 350(6265):aad2459. PMC: 4747105. DOI: 10.1126/science.aad2459. View

Billia F, Hauck L, Konecny F, Rao V, Shen J, Mak T . PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc Natl Acad Sci U S A. 2011; 108(23):9572-7. PMC: 3111326. DOI: 10.1073/pnas.1106291108. View

Kim J, Byun J, Choi I, Kim B, Jeong H, Jou I . PINK1 Deficiency Enhances Inflammatory Cytokine Release from Acutely Prepared Brain Slices. Exp Neurobiol. 2013; 22(1):38-44. PMC: 3620457. DOI: 10.5607/en.2013.22.1.38. View

Martinez D, Freeman W . Periglomerular cell action on mitral cells in olfactory bulb shown by current source density analysis. Brain Res. 1984; 308(2):223-33. DOI: 10.1016/0006-8993(84)91061-8. View

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

10.

Flinn L, Keatinge M, Bretaud S, Mortiboys H, Matsui H, De Felice E . TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency. Ann Neurol. 2013; 74(6):837-47. PMC: 4154126. DOI: 10.1002/ana.23999. View

11.

Wong-Riley M . Energy metabolism of the visual system. Eye Brain. 2012; 2:99-116. PMC: 3515641. DOI: 10.2147/EB.S9078. View

12.

Huisman E, Uylings H, Hoogland P . A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov Disord. 2004; 19(6):687-92. DOI: 10.1002/mds.10713. View

13.

Deas E, Piipari K, Machhada A, Li A, Gutierrez-del-Arroyo A, Withers D . PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice. Open Biol. 2014; 4:140051. PMC: 4042854. DOI: 10.1098/rsob.140051. View

14.

Mondelli V, Vernon A, Turkheimer F, Dazzan P, Pariante C . Brain microglia in psychiatric disorders. Lancet Psychiatry. 2017; 4(7):563-572. DOI: 10.1016/S2215-0366(17)30101-3. View

15.

Pickrell A, Huang C, Kennedy S, Ordureau A, Sideris D, Hoekstra J . Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress. Neuron. 2015; 87(2):371-81. PMC: 4803114. DOI: 10.1016/j.neuron.2015.06.034. View

16.

Gerasimenko O, Gerasimenko J . Mitochondrial function and malfunction in the pathophysiology of pancreatitis. Pflugers Arch. 2012; 464(1):89-99. DOI: 10.1007/s00424-012-1117-8. View

17.

Kluge M, Fetterman J, Vita J . Mitochondria and endothelial function. Circ Res. 2013; 112(8):1171-88. PMC: 3700369. DOI: 10.1161/CIRCRESAHA.111.300233. View

18.

Park M, ASHBY M, Erdemli G, Petersen O, Tepikin A . Perinuclear, perigranular and sub-plasmalemmal mitochondria have distinct functions in the regulation of cellular calcium transport. EMBO J. 2001; 20(8):1863-74. PMC: 125431. DOI: 10.1093/emboj/20.8.1863. View

19.

Zhang H, Bosch-Marce M, Shimoda L, Tan Y, Baek J, Wesley J . Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008; 283(16):10892-903. PMC: 2447655. DOI: 10.1074/jbc.M800102200. View

20.

McWilliams T, Prescott A, Allen G, Tamjar J, Munson M, Thomson C . mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol. 2016; 214(3):333-45. PMC: 4970326. DOI: 10.1083/jcb.201603039. View