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

Thomas G. McWilliams; Alan R. Prescott; Lambert Montava-Garriga; Graeme Ball; François Singh; Erica Barini; Miratul M. K. Muqit; Simon P.  Brooks; Ian G. Ganley

doi:10.1016/j.cmet.2017.12.008

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

Thomas G. McWilliams (Lead / Corresponding author), Alan R. Prescott, Lambert Montava-Garriga, Graeme Ball, François Singh, Erica Barini, Miratul M. K. Muqit, Simon P. Brooks, Ian G. Ganley (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

401 Citations (Scopus)

301 Downloads (Pure)

Abstract

Dysregulated mitophagy has been linked to Parkinson’s disease (PD) due to the role of 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 orchestrate mammalian mitochondrial integrity in a contextdependent fashion, and this has profound implications for our molecular understanding of vertebrate mitophagy.

Original language	English
Pages (from-to)	439-449.e5
Number of pages	17
Journal	Cell Metabolism
Volume	27
Issue number	2
Early online date	11 Jan 2018
DOIs	https://doi.org/10.1016/j.cmet.2017.12.008
Publication status	Published - 6 Feb 2018

Keywords

Autophagy
Dopaminergic
Mitochondria
Mitophagy
Neurodegeneration
Pancreas
Parkinson's disease
PINK1
Retina

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2017.12.008Licence: CC BY

Final Published VersionFinal published version, 5.69 MBLicence: CC BY

Evaluation of the Parkin Pathway in a Novel Mouse Model to Study Neuronal Mitophagy
Ganley, I. (Investigator) & Muqit, M. (Investigator)
8/03/16 → 7/03/17
Project: Research
Investigation of the Regulation of Rab GTPases by PINK1 (PhD Studentship)
Muqit, M. (Investigator)
Parkinson's UK
7/09/15 → 6/09/18
Project: Research
Dynamics of Fundamental Cellular Processes by Live Cell and Tissue Imaging
MacDonald, M. (Investigator), McGloin, D. (Investigator), McKenna, S. (Investigator), Storey, K. (Investigator), Swedlow, J. (Investigator) & Weijer, K. (Investigator)
Medical Research Council
1/01/13 → 31/12/17
Project: Research

Investigating how mitophagy is regulated by the metabolic context
Montava Garriga, L. (Author), Ganley, I. (Supervisor), 2020
Student thesis: Doctoral Thesis › Doctor of Philosophy

Ganley, Ian
- MRC PPU - Professor (Teaching and Research) of Cellular Homeostasis
Person: Academic

Cite this

@article{165ff6eb981448bc84e30f575752c2a0,

title = "Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand",

abstract = "Dysregulated mitophagy has been linked to Parkinson{\textquoteright}s disease (PD) due to the role of 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 orchestrate mammalian mitochondrial integrity in a contextdependent fashion, and this has profound implications for our molecular understanding of vertebrate mitophagy.",

keywords = "Autophagy, Dopaminergic, Mitochondria, Mitophagy, Neurodegeneration, Pancreas, Parkinson's disease, PINK1, Retina",

author = "McWilliams, {Thomas G.} and Prescott, {Alan R.} and Lambert Montava-Garriga and Graeme Ball and Fran{\c c}ois Singh and Erica Barini and Muqit, {Miratul M. K.} and Brooks, {Simon P.} and Ganley, {Ian G.}",

note = "This work was primarily funded by an MRC grant (MC_UU_12016/4) and an MJFF grant (11470). A co-author (Miratul Muqit) is also funded by Wellcome (101022/Z/13/Z).",

year = "2018",

month = feb,

day = "6",

doi = "10.1016/j.cmet.2017.12.008",

language = "English",

volume = "27",

pages = "439--449.e5",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Elsevier",

number = "2",

}

TY - JOUR

T1 - Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand

AU - McWilliams, Thomas G.

AU - Prescott, Alan R.

AU - Montava-Garriga, Lambert

AU - Ball, Graeme

AU - Singh, François

AU - Barini, Erica

AU - Muqit, Miratul M. K.

AU - Brooks, Simon P.

AU - Ganley, Ian G.

N1 - This work was primarily funded by an MRC grant (MC_UU_12016/4) and an MJFF grant (11470). A co-author (Miratul Muqit) is also funded by Wellcome (101022/Z/13/Z).

PY - 2018/2/6

Y1 - 2018/2/6

N2 - Dysregulated mitophagy has been linked to Parkinson’s disease (PD) due to the role of 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 orchestrate mammalian mitochondrial integrity in a contextdependent fashion, and this has profound implications for our molecular understanding of vertebrate mitophagy.

AB - Dysregulated mitophagy has been linked to Parkinson’s disease (PD) due to the role of 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 orchestrate mammalian mitochondrial integrity in a contextdependent fashion, and this has profound implications for our molecular understanding of vertebrate mitophagy.

KW - Autophagy

KW - Dopaminergic

KW - Mitochondria

KW - Mitophagy

KW - Neurodegeneration

KW - Pancreas

KW - Parkinson's disease

KW - PINK1

KW - Retina

U2 - 10.1016/j.cmet.2017.12.008

DO - 10.1016/j.cmet.2017.12.008

M3 - Article

C2 - 29337137

SN - 1550-4131

VL - 27

SP - 439-449.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Projects

Evaluation of the Parkin Pathway in a Novel Mouse Model to Study Neuronal Mitophagy

Investigation of the Regulation of Rab GTPases by PINK1 (PhD Studentship)

Dynamics of Fundamental Cellular Processes by Live Cell and Tissue Imaging

Student theses

Investigating how mitophagy is regulated by the metabolic context

Profiles

Ganley, Ian

Cite this