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.

Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

“…Another important question is how AMPK regulates mitophagy in skeletal muscle. In this regard, new PINK1–Parkin-independent mechanisms and the activation of specific, subcellular AMPK pools were reported [ 239 , 240 , 241 ].…”

The Imbalance of Mitochondrial Fusion/Fission Drives High-Glucose-Induced Vascular Injury

“…As a glucose and energy sensor, AMPK regulates the processes of both fusion and fission [ 15 , 21 , 22 , 36 , 46 , 47 ]. Meanwhile, AMPK has been reported to be involved in the development of diabetic vasculopathy [ 19 ].…”

Hypertrophy of Rat Skeletal Muscle Is Associated with Increased SIRT1/Akt/mTOR/S6 and Suppressed Sestrin2/SIRT3/FOXO1 Levels

“…The decreased levels of FOX1 in hypertrophied muscle, could mean suppressed degradation of proteins [ 8 ], however we were also interested in mitochondrial quality control during hypertrophy. Therefore, we measured the content of PINK1, since PINk1 signaling pathway regulates mitochondrial fission, and ubiquitylation, during mitophagy [ 40 ]. When PINK1 is activated by loss of the mitochondrial membrane potential or excessive production of ROS, this can readily lead to mitochondrial degradation via phosphorylation of Parkin.…”