Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy

Research output: Contribution to journalReview articlepeer-review

Standard

Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy. / Seabright, Alex P; Lai, Yu-Chiang.

In: Frontiers in Physiology, Vol. 11, 608474, 03.12.2020.

Research output: Contribution to journalReview articlepeer-review

Harvard

APA

Vancouver

Author

Bibtex

@article{e7e579ea0a23455caf1097ad989f0ac6,
title = "Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy",
abstract = "The selective removal of damaged mitochondria, also known as mitophagy, is an important mechanism that regulates mitochondrial quality control. Evidence suggests that mitophagy is adversely affected in aged skeletal muscle, and this is thought to contribute toward the age-related decline of muscle health. While our knowledge of the molecular mechanisms that regulate mitophagy are derived mostly from work in non-muscle cells, whether these mechanisms are conferred in muscle under physiological conditions has not been thoroughly investigated. Recent findings from our laboratory and those of others have made several novel contributions to this field. Herein, we consolidate current literature, including our recent work, while evaluating how ubiquitin-dependent mitophagy is regulated both in muscle and non-muscle cells through the steps of mitochondrial fission, ubiquitylation, and autophagosomal engulfment. During ubiquitin-dependent mitophagy in non-muscle cells, mitochondrial depolarization activates PINK1-Parkin signaling to elicit mitochondrial ubiquitylation. TANK-binding kinase 1 (TBK1) then activates autophagy receptors, which in turn, tether ubiquitylated mitochondria to autophagosomes prior to lysosomal degradation. In skeletal muscle, evidence supporting the involvement of PINK1-Parkin signaling in mitophagy is lacking. Instead, 5'-AMP-activated protein kinase (AMPK) is emerging as a critical regulator. Mechanistically, AMPK activation promotes mitochondrial fission before enhancing autophagosomal engulfment of damaged mitochondria possibly via TBK1. While TBK1 may be a point of convergence between PINK1-Parkin and AMPK signaling in muscle, the critical question that remains is: whether mitochondrial ubiquitylation is required for mitophagy. In future, improving understanding of molecular processes that regulate mitophagy in muscle will help to develop novel strategies to promote healthy aging.",
author = "Seabright, {Alex P} and Yu-Chiang Lai",
note = "Copyright {\textcopyright} 2020 Seabright and Lai.",
year = "2020",
month = dec,
day = "3",
doi = "10.3389/fphys.2020.608474",
language = "English",
volume = "11",
journal = "Frontiers in Physiology",
issn = "1664-042X",
publisher = "Frontiers",

}

RIS

TY - JOUR

T1 - Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy

AU - Seabright, Alex P

AU - Lai, Yu-Chiang

N1 - Copyright © 2020 Seabright and Lai.

PY - 2020/12/3

Y1 - 2020/12/3

N2 - The selective removal of damaged mitochondria, also known as mitophagy, is an important mechanism that regulates mitochondrial quality control. Evidence suggests that mitophagy is adversely affected in aged skeletal muscle, and this is thought to contribute toward the age-related decline of muscle health. While our knowledge of the molecular mechanisms that regulate mitophagy are derived mostly from work in non-muscle cells, whether these mechanisms are conferred in muscle under physiological conditions has not been thoroughly investigated. Recent findings from our laboratory and those of others have made several novel contributions to this field. Herein, we consolidate current literature, including our recent work, while evaluating how ubiquitin-dependent mitophagy is regulated both in muscle and non-muscle cells through the steps of mitochondrial fission, ubiquitylation, and autophagosomal engulfment. During ubiquitin-dependent mitophagy in non-muscle cells, mitochondrial depolarization activates PINK1-Parkin signaling to elicit mitochondrial ubiquitylation. TANK-binding kinase 1 (TBK1) then activates autophagy receptors, which in turn, tether ubiquitylated mitochondria to autophagosomes prior to lysosomal degradation. In skeletal muscle, evidence supporting the involvement of PINK1-Parkin signaling in mitophagy is lacking. Instead, 5'-AMP-activated protein kinase (AMPK) is emerging as a critical regulator. Mechanistically, AMPK activation promotes mitochondrial fission before enhancing autophagosomal engulfment of damaged mitochondria possibly via TBK1. While TBK1 may be a point of convergence between PINK1-Parkin and AMPK signaling in muscle, the critical question that remains is: whether mitochondrial ubiquitylation is required for mitophagy. In future, improving understanding of molecular processes that regulate mitophagy in muscle will help to develop novel strategies to promote healthy aging.

AB - The selective removal of damaged mitochondria, also known as mitophagy, is an important mechanism that regulates mitochondrial quality control. Evidence suggests that mitophagy is adversely affected in aged skeletal muscle, and this is thought to contribute toward the age-related decline of muscle health. While our knowledge of the molecular mechanisms that regulate mitophagy are derived mostly from work in non-muscle cells, whether these mechanisms are conferred in muscle under physiological conditions has not been thoroughly investigated. Recent findings from our laboratory and those of others have made several novel contributions to this field. Herein, we consolidate current literature, including our recent work, while evaluating how ubiquitin-dependent mitophagy is regulated both in muscle and non-muscle cells through the steps of mitochondrial fission, ubiquitylation, and autophagosomal engulfment. During ubiquitin-dependent mitophagy in non-muscle cells, mitochondrial depolarization activates PINK1-Parkin signaling to elicit mitochondrial ubiquitylation. TANK-binding kinase 1 (TBK1) then activates autophagy receptors, which in turn, tether ubiquitylated mitochondria to autophagosomes prior to lysosomal degradation. In skeletal muscle, evidence supporting the involvement of PINK1-Parkin signaling in mitophagy is lacking. Instead, 5'-AMP-activated protein kinase (AMPK) is emerging as a critical regulator. Mechanistically, AMPK activation promotes mitochondrial fission before enhancing autophagosomal engulfment of damaged mitochondria possibly via TBK1. While TBK1 may be a point of convergence between PINK1-Parkin and AMPK signaling in muscle, the critical question that remains is: whether mitochondrial ubiquitylation is required for mitophagy. In future, improving understanding of molecular processes that regulate mitophagy in muscle will help to develop novel strategies to promote healthy aging.

U2 - 10.3389/fphys.2020.608474

DO - 10.3389/fphys.2020.608474

M3 - Review article

C2 - 33343399

VL - 11

JO - Frontiers in Physiology

JF - Frontiers in Physiology

SN - 1664-042X

M1 - 608474

ER -