Mitophagy impairment mediated muscular atrophy: insights from the Drosophila model

Abstract

BACKGROUND: Muscular atrophy is a pathological process characterized by the progressive decline in muscle mass and function, which severely affects patients' quality of life. In recent years, the role of mitophagy, as an important mitochondrial quality control mechanism for maintaining intracellular homeostasis, has attracted significant attention in the context of muscle atrophy. Drosophila, as a classical model organism, has become a crucial tool for studying the connection between muscle atrophy and mitophagy mechanism due to its conserved muscle functional structure and straightforward genetic manipulation. OBJECTIVE: To review the molecular mechanism of mitophagy dysfunction in muscular atrophy and to summarize the research progress of relevant Drosophila models in this field, with the aim of providing new insights and directions for the study of the pathological mechanism and the development of therapeutic strategies for muscular atrophy. METHODS: PubMed and China National Knowledge Infrastructure databases were searched using keywords including 'skeletal muscle, muscle regenerate, denervation muscle atrophy, muscle atrophy, sarcopenia, drosophila, drosophila melanogaster, mitophagy, mitochondrial dysfunction' and 'muscle atrophy, skeletal muscle, muscle regeneration, sarcopenia, denervation muscle atrophy, Drosophila, mitophagy, mitochondrial dysfunction'. The search period was from January 2001 to February 2025. After screening, 68 articles were included for review. RESULTS AND CONCLUSION: Studies using Drosophila models indicate that mitophagy plays a critical role in the development of muscle atrophy. Mitophagy dysfunction leads to the accumulation of damaged mitochondria in muscle cells, triggering oxidative stress, energy metabolism disorders, and inducing myocyte apoptosis, thereby exacerbating muscle atrophy. Furthermore, Drosophila models have shown great advantages in screening potential therapeutic targets and identifying intervention strategies, providing new avenues for mechanistic research and therapeutic development for muscle atrophy. By summarizing the findings from Drosophila models, this review emphasizes the strategy of treating muscle atrophy by modulating mitophagy mechanisms, highlights the unique advantages of Drosophila models in studying the molecular mechanisms of mitophagy and muscle atrophy, and suggests that future research should integrate translational medicine, high-throughput molecular screening, and multi-omics approaches to further explore unknown molecular mechanisms and new therapeutic targets.

1. Introduction

Muscle atrophy is a pathological process associated with disease, aging, and genetic factors, characterized by reduced muscle volume, decreased muscle fiber number, and diminished muscle strength. With the global aging population, it has become a significant public health issue, yet the exact molecular mechanisms remain largely unknown. Mitochondria, as the 'powerhouse' of the cell, play a crucial role in energy metabolism. Recent research has made significant progress in targeting mitochondria to ameliorate clinical symptoms of muscle atrophy, with studies showing that modulating mitochondrial function can effectively delay muscle degeneration.

Mitophagy, a selective autophagy that degrades damaged mitochondria, is critical for maintaining cellular homeostasis in muscle cells. It operates via two main mechanisms: ubiquitin-dependent and ubiquitin-independent pathways. The ubiquitin-dependent pathway relies on ubiquitination of mitochondrial surface proteins, with the most typical being the PINK1/Parkin signaling pathway, which ubiquitinates damaged mitochondria and targets them for autophagic degradation. The ubiquitin-independent pathway involves mitophagy receptors that directly bind to microtubule-associated protein 1 light chain 3 (LC3) to mediate mitophagy.