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 (...

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Bibliographic Details
Published in:Molecular and cellular biology 2014-04, Vol.34 (8), p.1427-1437
Main Authors: Ng, Andy Cheuk-Him, Baird, Stephen D., Screaton, Robert A.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Cells, Cultured
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Energy Metabolism - physiology
HSP40 Heat-Shock Proteins - genetics
HSP40 Heat-Shock Proteins - metabolism
Humans
Membrane Potential, Mitochondrial - genetics
Membrane Potential, Mitochondrial - physiology
Mitochondria - genetics
Mitochondria - metabolism
Signal Transduction - physiology
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Summary: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 F 1 F o 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.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.01021-13