bims-mitpro 2025-03-16 papers

Issue of 2025–03–16
three papers selected by
Andreas Kohler, Umeå University

J Biol Chem. 2025 Mar 12. pii: S0021-9258(25)00252-2. [Epub ahead of print] 108403

The E3 ubiquitin ligase RNF126 facilitates quality control of unimported mitochondrial membrane proteins.

Di Liu, Xin-Yu Huo, Xiaoli Zhang, Zai-Rong Zhang.

Pathological stress can lead to failure in the translocation of mitochondrial proteins, resulting in accumulation of unimported proteins within the cytosol and upregulation of proteasome for their quality control. Malfunction or delay in protein clearance causes dysregulation of mitochondrial protein homeostasis, cellular toxicity, and diseases. Ubiquilins (UBQLNs) are known to serve as chaperone which associates with unimported mitochondrial membrane protein precursors, and facilitates their proteasomal degradation. However, how UBQLN-engaged proteins are ubiquitinated and efficiently targeted to the proteasome are poorly understood. Here, using mitochondrial membrane protein ATP5G1 as a model substrate, we report that E3 ubiquitin ligase RNF126 interacts with substrate-engaged UBQLN1, thereby promoting ubiquitination and degradation of unimported proteins during mitochondrial stress. We find that UBQLN1's ubiquitin-associated domain (UBA) recruits RNF126 when its middle domain binds to unimported protein substrate. Recombinant RNF126 forms ternary complex with UBQLN1 and pATP5G1 in vitro and catalyzes ubiquitination of UBQLN1-bound ATP5G1. Without RNF126, proteasomal degradation of ATP5G1 was compromised. These results explain how RNF126 and ubiquilins interplay to ensure specific quality control of unimported mitochondrial membrane proteins under pathophysiological conditions.

Keywords: ATP synthase F(0) complex subunit C1; RNF126; Ubiquilin; cytosolic quality control; mitochondrial membrane protein degradation

DOI: https://doi.org/10.1016/j.jbc.2025.108403

Science. 2025 Mar 13. eadu6445

Structure of human PINK1 at a mitochondrial TOM-VDAC array.

Sylvie Callegari, Nicholas S Kirk, Zhong Yan Gan, Toby Dite, Simon A Cobbold, Andrew Leis, Laura F Dagley, Alisa Glukhova, David Komander.

Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson's Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.

DOI: https://doi.org/10.1126/science.adu6445

Trends Cell Biol. 2025 Mar 07. pii: S0962-8924(25)00039-X. [Epub ahead of print]

Quality control of mitochondrial nucleoids.

Hao Liu, Haixia Zhuang, Du Feng.

Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.

Keywords: mitochondria; mitophagy; mtDNA; nucleoid-phagy; nucleoids

DOI: https://doi.org/10.1016/j.tcb.2025.02.005