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Lookup NU author(s): Dr Rhoda StefanatosORCiD, Dr Fiona Robertson, Dr Tetsushi Kataura, Professor Viktor KorolchukORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. 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 maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation 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 a 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, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
Author(s): Stefanatos R, Robertson F, Castejon-Vega B, Yu Y, Uribe AH, Myers K, Kataura T, Korolchuk VI, Maddocks ODK, Martins LM, Sanz A
Publication type: Article
Publication status: Published
Journal: EMBO Reports
Year: 2025
Pages: Epub ahead of print
Online publication date: 17/03/2025
Acceptance date: 21/02/2025
Date deposited: 09/04/2025
ISSN (print): 1469-221X
ISSN (electronic): 1469-3178
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s44319-025-00416-6
DOI: 10.1038/s44319-025-00416-6
Data Access Statement: RNA-sequencing data are available under accession number GSE237015 on the NCBI Gene Expression Omnibus database [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE237015]. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD043791 [https://www.ebi.ac.uk/pride/archive/projects/PXD043791]. The source data of this paper are collected in the following database record: https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44319-025-00416-6
PubMed id: 40097814
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