bims-mitran 2025-03-09 papers

Issue of 2025–03–09
three papers selected by
Andreas Kohler, Umeå University

J Cell Biol. 2025 Apr 07. pii: e202407110. [Epub ahead of print]224(4):

Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.

Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn.

Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to the mitochondria posttranslationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome at the mitochondrial surface in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membranes. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.

DOI: https://doi.org/10.1083/jcb.202407110

Sci Adv. 2025 Mar 07. 11(10): eadr0690

Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.

Yu Nie, Kornélia Szebényi, Lea M D Wenger, András Lakatos, Patrick F Chinnery.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.

DOI: https://doi.org/10.1126/sciadv.adr0690

Nat Commun. 2025 Mar 06. 16(1): 2250

Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.

Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.

Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.

DOI: https://doi.org/10.1038/s41467-025-57286-8