UBA5 deficiency disrupts mitochondrial autophagy via the PINK1–parkin pathway and impairs myoblast proliferation

TL;DR

This study shows that UBA5 deficiency disrupts mitochondrial autophagy and harms myoblast proliferation through the PINK1–parkin pathway.

Contribution

The paper reveals a new role for UBA5 in mitochondrial quality control via UFMylation and mitophagy.

Findings

UBA5 loss leads to accumulation of damaged mitochondria and increased ROS.

UBA5 deficiency causes p53 activation, DNA damage, and apoptosis.

Mitophagy is inefficient in UBA5-deficient cells despite PINK1–Parkin activation.

Abstract

Maintaining a healthy and dynamic mitochondrial network is essential for development and for cellular adaptation to physiological and stress conditions. UFMylation is an emerging post-translational modification, yet its involvement in mitochondrial quality control has remained largely unexplored. Here, we establish a previously unrecognized functional link between the UFMylation machinery and mitochondrial homeostasis by identifying the E1-like activating enzyme UBA5 as a key regulator of mitochondrial quality control. We show that UBA5 loss disrupts mitochondrial homeostasis, leading to persistent accumulation of damaged mitochondria and increased ROS accumulation, which in turn triggers p53 activation and DNA damage responses, enforces p21-associated G2/M arrest, and promotes early apoptosis. Mechanistically, although the PINK1–Parkin damage response is engaged, mitophagy execution is inefficient in UBA5-deficient cells, resulting in impaired clearance of dysfunctional mitochondria and exacerbated oxidative stress. Collectively, our findings uncover a previously unreported UFMylation–mitophagy axis and expand current understanding of how UBA5 governs mitochondrial homeostasis and cell fate decisions.

The online version contains supplementary material available at 10.1186/s40659-026-00676-z.

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