Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria

Janne P Purhonen, Rishi Banerjee, Vilma Wanne, Nina Sipari, Matthias Morgelin, Vineta Fellman, Jukka Kallijärvi

Research output: Contribution to journalArticleScientificpeer-review


Accumulating evidence suggests mitochondria as key modulators of normal
and premature aging, yet whether primary oxidative phosphorylation
(OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we
show that mice with severe isolated respiratory complex III (CIII) deficiency
display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular
senescence in the affected organs such as liver and kidney, and a systemic
phenotype resembling juvenile-onset progeroid syndromes. Mechanistically,
CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against
lack of energy and biosynthetic precursors. Transgenic alternative oxidase
dampens mitochondrial integrated stress response and the c-MYC induction,
suppresses the illicit proliferation, and prevents juvenile lethality despite that
canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC
with the dominant-negative Omomyc protein relieves the DNA damage in CIIIdeficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency
to genomic instability and progeroid pathogenesis and suggest that targeting
c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial
Original languageEnglish
JournalNature Communications
Issue number1
Pages (from-to)1-23
Number of pages23
Publication statusPublished - 24 Apr 2023
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1182 Biochemistry, cell and molecular biology
  • Fetal-growth-retardation
  • De-novo mutations
  • Stress-response
  • Iron-overload
  • Progenitor cells
  • Lactic-acidosis
  • Slc25a24 cause
  • G(2) arrest
  • Liver
  • Mice

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