Authors
Kexin Shi, Hao Liu, Hong Xu, Weina Shang, Liquan Wang, Chao Tong
Published in
Cell & bioscience. Jun 19, 2026. Epub Jun 19, 2026.
Abstract
Mitochondrial proteases are essential for mitochondrial protein import and constitute the core of the organelle's intrinsic protein quality control system. However, their physiological functions across tissues, as well as their influence on cytosolic proteostasis, remain incompletely understood.
We generated loss- and gain-of-function alleles for 15 conserved mitochondrial proteases in Drosophila melanogaster to systematically dissect their in vivo functions. Disruption of specific proteases caused male sterility or organismal lethality, whereas tissue-specific knockouts in the eye, muscle, or fat body led to mitochondrial protein aggregates, structural defects, and age-dependent degeneration. Loss of UQCR-C1 or Afg3l2 robustly increased mitophagy, while overexpression of several proteases severely impaired muscle integrity. Loss of UQCR-C1, Mppa, or CG11771 promoted HTT72Q aggregation, and reducing UQCR-C1 or Afg3l2 markedly elevated cytosolic HTT72Q levels. Conversely, overexpressing Mppa-but with reduced efficacy in its disease-associated variants-suppressed HTT96Q aggregation and neuronal toxicity. Mppa forms a complex with UQCR-C1 to regulate mitochondrial pre-protein processing and import, indicating that enhancing mitochondrial protein import is sufficient to alleviate cytosolic proteotoxic stress caused by HTT polyglutamine (polyQ) proteins.
This work establishes a comprehensive in vivo resource for mitochondrial protease functions and their roles in shaping cytosolic proteostasis.
PMID:
42321946
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.
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