A stress-adapted fiber state promotes clonal expansion of deleted mitochondrial DNA
Mitochondrial DNA (mtDNA) depletion and multiple deletions frequently coexist in mitochondrial disease, neurodegeneration, and aging, yet how the two relate and why deletions accumulate focally remain unresolved. Here, longitudinal bulk and in situ analyses of Mpv17 −/− murine muscle reveal that a compensatory rise in mitochondrial transcripts per mtDNA initially offsets severe, uniform mtDNA depletion, preserving the respiratory chain. However, this response carries a delayed cost: by six months transcripts decline, mtDNA deletions emerge, and respiratory-deficient fibers appear. Paradoxically, fibers harboring deletions accumulate supra-physiological amounts of mtDNA, despite prior depletion. This expansion is invariably accompanied by elevated Hsp60, and the same holds in human mitochondrial myopathy. We propose that depletion reprograms mitochondrial DNA and RNA metabolism, inadvertently promoting deletion formation and creating an Hsp60-high fiber state permissive for clonal expansion. Therefore, depletion and multiple deletions can be sequential phases of a common degenerative process, relevant also to aging and neurodegeneration.
Authors
- Aleck W.E. Jones
- Mats F. Nilsson (ORCID: https://orcid.org/0000-0001-9985-0387)
- Martin A.M. Reijns (ORCID: https://orcid.org/0000-0002-5048-2752)
- Robert D. S. Pitceathly (ORCID: https://orcid.org/0000-0002-6123-4551)
- Christos Proukakis (ORCID: https://orcid.org/0000-0001-6423-6539)
- Chloe F. Moss (ORCID: https://orcid.org/0000-0002-7721-2744)
- Ian James Holt (ORCID: https://orcid.org/0000-0001-5468-0193)
- Antonella Spinazzola (ORCID: https://orcid.org/0000-0003-4242-8091)
- Samantha Davidson
- Ilaria Dalla Rosa (ORCID: https://orcid.org/0000-0003-4801-2396)
- Sara Ricciardi (ORCID: https://orcid.org/0000-0001-8124-432X)
- Renata Kabiljo (ORCID: https://orcid.org/0000-0002-5183-4844)
- Shar-Yin Naomi Huang (ORCID: https://orcid.org/0000-0002-4772-428X)
- Radha Desai (ORCID: https://orcid.org/0000-0001-5642-0168)
- Diego Pérez‐Rodríguez (ORCID: https://orcid.org/0000-0003-4903-3914)
- Monika Hofer (ORCID: https://orcid.org/0000-0002-8656-2324)
- Tamara L. Hill
- Joanna Poulton (ORCID: https://orcid.org/0000-0002-2460-5587)
- Aine Moylett
- Anastasia Magoulopoulou (ORCID: https://orcid.org/0000-0002-2175-7198)
- Robert W. Taylor
- Rebecca Lasalandra
- Yves Pommier
- Tengfei Wan
- Charlotte Zierz
- J. Paul Simons
- Melissa L. Salazar
Institutions
- Ikerbasque (ES)
- National Institutes of Health (US)
- Stockholm University (SE)
- Science for Life Laboratory (SE)
- The Royal Free Hospital (GB)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- University of Oxford (GB)
- Amyloidosis Foundation (US)
- National Cancer Institute (US)
- Oxford University Hospitals NHS Trust (GB)
- Center for Cancer Research (US)
- National Hospital for Neurology and Neurosurgery (GB)
- Roland Hill (United Kingdom) (GB)
- Institute of Genetics and Cancer (GB)
- MRC Human Genetics Unit (GB)
- UCL Queen Square Institute of Neurology (GB)
- National Institute for Medical Research (GB)
- University College London (GB)
- Newcastle University (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-10-29
- DOI
- https://doi.org/10.1016/j.celrep.2026.117995
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- LifeArc
- French Muscular Dystrophy Association
- Brain Research UK
- Ministerio de Ciencia, Innovación y Universidades
- National Institute for Health and Care Research
- British Heart Foundation
- European Commission
- Great Ormond Street Hospital Charity
- Consejo Nacional de Ciencia y Tecnología
- Vetenskapsrådet
- Muscular Dystrophy UK
- Osasun Saila, Eusko Jaurlaritzako
- Lily Foundation
- Medical Research Council
- Instituto de Salud Carlos III
- Wellcome Trust Centre for Mitochondrial Research
- National Cancer Institute