Biology subjects

Tolla, E.

Publications and source records attributed to Tolla, E..

3 recordsLinked to original sources

bioRxiv2026

A conserved mechanism for regulation of mtDNA copy number in eukaryotes

Mitochondrial mass and mitochondrial DNA (mtDNA) copy number are coupled to metabolic demand at the cellular, tissue and organismal level, however, the molecular basis for homeostatic regulation of mtDNA is not understood. Here we show that mitochondria and mtDNA copy number are regulated by compartmentalisation of iron-sulfur (Fe-S) clusters, glutathione and cysteine, a mechanism we exemplify in model systems ranging from plants to human cells. Using genome-wide CRISPR screens we discovered that the mitochondrial ABC-family transporter, ABCB7, is a negative regulator of mtDNA copy number. Partial silencing of ABCB7 in human cells increased mtDNA 2-3 fold, enhancing mitochondrial mass and function. ABCB7 silencing compelled co-incident mitochondrial accumulation and cytosolic depletion of Fe-S clusters, simultaneously engaging the cellular iron starvation response and stabilising the mitochondrial glutathione transporter, SLC25A39. Transport of glutathione from the cytosol into mitochondria was co-incident with mitochondrial cysteine accumulation and cytosolic cysteine depletion, which was necessary and sufficient to increase mtDNA copy number in an integrated stress response-dependent fashion, with induction of PGC1{beta} and ERR. Silencing or partial loss of function mutations in the ABCB7 homologs of D.melanogaster, S.cerevisiae and A. thaliana elicited similar increases of mtDNA within these organisms. These data reveal a fundamental metabolic logic coupling compartmentalisation of redox co-factors to organellar genome content; a conserved axis across eukaryotes that pre-dates several elements of the mtDNA replication machinery.

cell biology↗

bioRxiv2025

Hypothalamic deiodinase type-3 establishes the period of circannual interval timing in mammals

Animals respond to environmental cues to time phenological events, but the intrinsic mechanism of circannual timing remains elusive. We used transcriptomic sequencing and frequent sampling of multiple hypothalamic nuclei in Djungarian hamster to examine the neural and molecular architecture of circannual interval timing. Our study identified three distinct phases of transcript changes, with deiodinase type-3 (Dio3) expression activated during the early induction phase. Subsequent work demonstrated that targeted mutation of Dio3 using CRISPR-Cas resulted in a shorter period for circannual interval timing. Hamsters that are non-responsive to short photoperiod and fail to show any winter adaptations do not display changes in Dio3 expression do not show any change in body mass or pelage. Our work demonstrates that changes in Dio3 induction is essential for setting the period of circannual interval timing.

neuroscience↗

bioRxiv2023

Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade

The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented1. While mitochondrial DNA (mtDNA) mutations have been associated with both improved and worsened prognoses in several tumour lineages1-,3, whether these mutations are drivers or exert any functional effect on tumour biology remains controversial. Here we discovered that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology4 we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux without major effects on oxygen consumption, driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment in both mice and humans, promoting an anti- tumour immune response characterised by loss of resident neutrophils. This subsequently sensitised tumours bearing high mtDNA mutant heteroplasmy to immune checkpoint blockade, with phenocopy of key metabolic changes being sufficient to mediate this effect. Strikingly, patient lesions bearing >50% mtDNA mutation heteroplasmy also demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

cancer biology↗