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Blocking dMIC60 Oxidation Drives Mitochondrial-Nuclear Crosstalk and Promotes Resilience

ABSTRACT: Mitochondria communicate their functional and redox states to the nucleus to coordinate cellular adaptation, but how proteins that regulate mitochondrial ultrastructure participate in this signaling remains incompletely understood. MIC60 is a core component of the mitochondrial contact site and cristae organizing system and is susceptible to redox-dependent regulation. Here, we investigate the molecular and physiological consequences of blocking oxidation of Drosophila MIC60 (dMIC60). Transcriptomic analysis reveals coordinated increases in mitochondrial, metabolic, and nuclear gene programs in female flies expressing oxidation-resistant dMIC60-CS compared with those expressing wild-type dMIC60-WT. Notably, timeout, a TIMELESS-family gene implicated in circadian regulation and genome maintenance, is among the most highly upregulated genes. dMIC60-CS females exhibit increased sleep, extended lifespan, and improved locomotor performance, consistent with the transcriptomic signatures. Mitochondrial ultrastructure and membrane potential are preserved, indicating that the transcriptional response is not associated with overt mitochondrial dysfunction. In MIC60-null HeLa cells, dMIC60-CS expression similarly increases TIMELESS abundance and resistance to oxidative stress. These findings identify the dMIC60 oxidation state as a potential regulator of a conserved mitochondria-to-nucleus signaling pathway that coordinates metabolism, stress resistance, and organismal physiology.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE346353 | GEO | 2026/09/07

REPOSITORIES: GEO

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Project description:Mitochondria generate signals of adaptation that regulate nuclear genes expression via retrograde signaling. But this phenomenon is complexified when qualitatively different mitochondria and mitochondrial DNA (mtDNA) coexist within cells. Although this cellular state of heteroplasmy leads to divergent phenotypes clinically, its consequences on cellular function and the cellular transcriptome are unknown. To interrogate this phenomenon, we generated somatic cell cybrids harboring increasing levels of a common mtDNA mutation (tRNALeu(UUR) 3243A>G) and mapped the resulting cellular phenotypes and transcriptional profiles across the complete range of heteroplasmy. Small increases in mutant mtDNAs caused relatively modest defect in mitochondrial oxidative capacity, but resulted in sharp transitions in mitochondrial ultrastructure and in the nuclear and mitochondrial transcriptomes, with the critical functional threshold corresponding to the induction of epigenetic regulatory systems. Principal component analysis underscores how each heteroplasmy level occupies a different "transcriptional space", with low levels heteroplasmy (20-30%) producing a dose-response linear progression in one direction, and mutationload of 50, 60 and 90% producing changes in the opposite direction. Hence, subtle changes in mitochondrial energetics can act through the epigenome to generate the phenotypes of the common “complex” diseases. Cells were generated by transferring the wildtype (3243A) and mutant (3243G) mtDNAs from a heteroplasmic 3243A>G patient’s lymphoblastoid cell line into 143B(TK-) mtDNA-deficient (ρo) cells and selected for transmitochondrial cybrids. Subsequent mtDNA depletion, reamplification, and cloning (Wiseman and Attardi, 1978) resulted in a series of stable cybrids harboring approximately 0, 20, 30, 50, 60, 90, and 100% 3243G mutant mtDNAs. Total RNA extracted from each cell line was then extracted, depleted of rRNA, and measured in sequenced in triplicates.

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Blocking dMIC60 Oxidation Drives Mitochondrial-Nuclear Crosstalk and Promotes Resilience

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