bims-mitpro 2025-10-12 papers

Issue of 2025–10–12
two papers selected by
Andreas Kohler, Umeå University

Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122

STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.

Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.

The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.

Keywords: cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis

DOI: https://doi.org/10.1073/pnas.2508809122

Science. 2025 Oct 09. 390(6769): 156-163

Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.

Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.

Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.

DOI: https://doi.org/10.1126/science.adr5438