Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity.
The tumorous imaginal disc 1 (TID1) protein localizes mainly to the mitochondrial compartment, wherein its function remains largely unknown. Here we report that TID1 regulates the steady-state homogeneity of the mitochondrial membrane potential (Δψ) and maintains the integrity of mitochondrial DNA (mtDNA). Silencing of TID1 with RNA interference leads to changes in the distribution of Δψ along the mitochondrial network, characterized by an increase in Δψ in focal regions. This effect can be rescued by ectopic expression of a TID1 construct with an intact J domain. Chronic treatment with a low dose of oligomycin, an inhibitor of F1Fo ATP synthase, decreases the cellular ATP content and phenocopies TID1 loss of function, indicating a connection between the disruption of mitochondrial bioenergetics and hyperpolarization. Prolonged silencing of TID1 or low-dose oligomycin treatment leads to the loss of mtDNA and the consequent inhibition of oxygen consumption. Biochemical and colocalization data indicate that complex I aggregation underlies the focal accumulation of Δψ in TID1-silenced cells. Given that TID1 is proposed to function as a cochaperone, these data show that TID1 prevents complex I aggregation and support the existence of a TID1-mediated stress response to ATP synthase inhibition.
Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Andy Cheuk-Him
AC
Ng
Stephen D
SD
Baird
Robert A
RA
Screaton
D000255:Adenosine Triphosphate / Q000378:metabolism; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D004272:DNA, Mitochondrial; C120664:DNAJA3 protein, human; D050956:HSP40 Heat-Shock Proteins; D000255:Adenosine Triphosphate