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Developmental mitochondrial Complex I activity determines lifespan

ABSTRACT: Aberrant mitochondrial function has been linked to a growing number of human diseases. Observations from in vivo models with altered mitochondrial function suggest that maladaptations to mitochondrial dysfunction may underlie disease pathology. We hypothesised that the severity of this maladaptation is influenced by the organism's plasticity when mitochondrial dysfunction occurs. To investigate this, we utilised inducible fly models of mitochondrial complex I (CI) dysfunction to impair mitochondrial function from early development or after eclosion. Here, we demonstrate that early-life (developmental) mitochondrial dysfunction leads to marked reductions in survival and stress resistance in adulthood, whereas flies with CI dysfunction initiated in adulthood are long-lived and stress-resistant despite experiencing up to a 75% reduction in CI activity. We performed molecular characterisation of these two populations of CI-compromised flies-short- and long-lived-and found that short-lived flies exhibit unique transcriptomic, proteomic, and metabolomic profiles, with significant overlap across distinct models of CI dysfunction. Our findings indicate that early CI dysfunction triggers a maladaptive response drastically reducing survival, whereas CI depletion in adulthood does not compromise survival or stress resistance.

SUBMITTER: Rhoda Stefanatos

PROVIDER: S-SCDT-10_1038-S44319-025-00416-6 | biostudies-other |

REPOSITORIES: biostudies-other

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Developmental mitochondrial complex I activity determines lifespan

Project description:Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that adaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of these maladaptations could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to an 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic and metabolomic responses which overlap significantly in discreet models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits an adaptive response which severely reduces survival, while CI depletion from adulthood is not sufficient to reduce survival and stress resistance.

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Developmental mitochondrial complex I activity determines lifespan

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