bims-mitran 2026-09-13 papers

Issue of 2026–09–13
three papers selected by
Andreas Kohler, Umeå University

Biochim Biophys Acta Mol Cell Res. 2026 Sep 06. pii: S0167-4889(26)00119-9. [Epub ahead of print]1873(8): 120220

Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.

Tânia Catarina Medeiros, Gaetano Calabrese.

Mitochondria are central hubs of cellular metabolism that harbor their own genome (mtDNA), whose maintenance is essential for both cellular and organismal homeostasis. Unlike nuclear DNA, mtDNA replicates continuously throughout the cell cycle, rendering it particularly sensitive to changes in metabolic state. Emerging evidence indicates that mtDNA homeostasis is not governed solely by dedicated replication factors but is tightly coupled to cellular metabolism. In this review, we discuss how metabolic networks shape mtDNA maintenance through three interconnected layers: mitochondrial nucleotide pools, metabolic control of the replication machinery, and stress-response pathways. This conceptual framework underscores the direct role of metabolic state in governing mtDNA replication, stability, and quality control, with significant implications for mitochondrial disease and therapeutic strategies.

Keywords: Integrated stress response (ISR); Metabolism; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Nucleotides; Replication machinery

DOI: https://doi.org/10.1016/j.bbamcr.2026.120220

Aging Cell. 2026 Sep;25(9): e70710

Mitochondrial Haplotype Shapes the Trajectory of Ovarian Aging in Genetically Heterogeneous Rats.

Subhasri Biswas, Hoang V M Nguyen, Aubrey Converse, Satoshi Matsuzaki, Michael T Kinter, Kenneth M Humphries, Willard M Freeman, Sarah R Ocañas, Arlan Richardson, Francesca E Duncan, Tommy L Lewis, Michael B Stout.

Ovarian aging leads to permanent reproductive senescence and systemic hormonal changes that predispose women to age-associated comorbidities. Despite these observations, the intrinsic mechanisms driving age-related ovarian decline are poorly defined. Mitochondrial DNA (mtDNA) mutations and instability are strongly associated with aging; however, it remains unknown if naturally occurring mitochondrial genetic variation influences the trajectory of ovarian aging. To address this, we compared two genetically heterogeneous rat cohorts (OKC-HETB and OKC-HETW) that differ in mitochondrial haplotype on a randomized but equivalently distributed nuclear background. The OKC-HETW haplotype was associated with accelerated loss of primordial follicles and pathological remodeling marked by fibrosis, macrophage infiltration, and multinucleated giant cells. These tissue-level pathologies were paralleled by mitochondrial dysfunction, characterized by decreased respiratory complex activity, ATP production, and mtDNA copy number. Mechanistically, we identified a haplotype-specific defect in mitochondrial genome maintenance. Although TFAM expression was normal, and total TFAM protein was elevated, OKC-HETW ovaries showed reduced mitochondrial TFAM abundance, TFAM-mtDNA binding, and TOMM20, suggesting that impaired TOMM20-mediated import is associated with compromised mitochondrial genomic stability. Longitudinal transcriptomic and proteomic analyses further indicate that mitochondrial haplotype influences the rate of ovarian aging, with OKC-HETW ovaries showing accelerated activation of inflammatory and fibrotic pathways alongside suppressed proteostasis and mitochondrial function. These defects corresponded to impairments in ovulation and a trend toward worsening oocyte quality. Collectively, our findings identify mitochondrial haplotype as a heritable modifier of ovarian aging rate that acts in concert with the nuclear genome, and a putative target for preserving ovarian function and female healthspan.

Keywords: anti‐Müllerian hormone; follicle; haplogroup; menopause; oxidative phosphorylation; rat; reproductive senescence

DOI: https://doi.org/10.1111/acel.70710

Front Cell Dev Biol. 2026 ;14 1840428

Spatiotemporal control of mitoribosome-mediated metabolic reprogramming in cancer: implications for heterogeneity and therapeutic targeting.

Xiaojie Chen, Weidong Wang, Fangxin Shen, Zhiwei Zhao.

Mitochondrial ribosomes (mitoribosomes), particularly mitochondrial ribosomal subunit proteins (MRPS), are emerging as contributors to cancer metabolic reprogramming. Rather than static components of mitochondrial translation, MRPS exhibit pronounced spatiotemporal heterogeneity that shapes tumor metabolic plasticity and therapeutic response. This review systematically summarizes evidence that MRPS functions are dynamically regulated across tumor progression and spatial microenvironments. Temporally, MRPS mediate metabolic switching between oxidative phosphorylation (OXPHOS) and glycolysis, contributing to metabolic adaptation, treatment resistance, and tumor evolution. Spatially, MRPS display context-dependent functions across tumor regions, cancer types, and metabolic microenvironments, thereby contributing to intratumoral metabolic diversity. We further highlight that MRPS-associated metabolic plasticity is linked with lactate metabolism and hypoxia-inducible factor (HIF) signaling, forming feedback networks associated with tumor growth, immune escape, and therapy resistance. This spatiotemporal regulatory axis challenges the traditional static view of mitochondrial dysfunction in cancer. Targeting MRPS-associated metabolic adaptation may provide therapeutic opportunities beyond the traditional Warburg framework. Emerging technologies, including lactate-sensitive nanoprobes, reactive oxygen species (ROS)-responsive delivery systems, and MRPS-related imaging platforms, may support metabolic monitoring and targeted therapeutic intervention. Collectively, this framework links mitochondrial translation with tumor metabolism and microenvironmental regulation, providing additional insight into metabolic adaptation in cancer.

Keywords: MRPs; cancer metabolic reprogramming; mitoribosomes; spatial heterogeneity; targeted therapy; temporal heterogeneity

DOI: https://doi.org/10.3389/fcell.2026.1840428