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1 Biology, York University, Toronto, Ontario, Canada
2 Kinesiology and Health Science, York University, Toronto, Ontario, Canada
3 Hospital for Sick Children, Toronto, Ontario, Canada
4 Kinesiology and Health Science, York University, Toronto, Ontario, Canada; Biology, York University, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: dhood{at}yorku.ca.
Defects in the mitochondrial genome evoke distinctive adaptive responses in the nuclear genome, leading to altered mitochondrial biogenesis. Here we used C2C12 cells chemically depleted of mitochondrial DNA (mtDNA; rho- cells) and fibroblasts obtained from a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) to examine adaptations of the protein import machinery, as well as transcription factors involved in mitochondrial biogenesis. In rho- cells, Tom20 and Tim23 protein levels were reduced by 25% and 59% of control, respectively. No change was observed in heat shock protein 60 (Hsp60), but mitochondrial heat shock protein 70 (mtHsp70) was induced by 2-fold in rho- , relative to control cells. These changes were accompanied by a 21% increase in enhanced yellow fluorescent protein (EYFP) import into mitochondria in rho- cells (P < 0.05). In contrast, in MELAS cells mtHsp70 was elevated by 70%, while Tom20 and Tom34 protein levels were increased by 45% and 112% relative to control values, respectively, and Hsp60 was reduced by 25%. However, EYFP import into the matrix was not impaired in MELAS cells. Overexpression of Tom34 in C2C12 cells resulted in an 18% (P < 0.05) increase in EYFP import into mitochondria. In rho- cells, nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (Tfam) protein levels declined by 33% and 54%, respectively, while no change was observed for peroxisome proliferator-activated receptor gamma (PPAR-
) coactivator-1 (PGC-1
). Tfam was increased by 40% and COX IV levels by 53% in MELAS cells. Rho- cells displayed a reduced rate of whole cell oxygen consumption (VO2) and ATP, concomitant with a 2-fold increase in lactate levels (P < 0.05). In contrast, in electrically stimulated C2C12 cells, 109%, 78%, 60% and 67% increases were observed in mtDNA, VO2, COX activity and Tom34 levels, respectively (P < 0.05). Our findings suggest that compensatory adaptations occurred in the mitochondrial import pathway to maintain a normal rate of import in response to mtDNA defects, and our data support a role for contractile activity in reducing the pathophysiology associated with mtDNA depletion. Since the expression of nuclear-encoded transcription factors and protein import machinery components was dependent on the type of mtDNA defect, these findings suggest the involvement of distinct signaling cascades, each dependent on the type of mitochondrial defect, resulting in divergent changes in nuclear gene expression patterns.
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