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CELLULAR METABOLISM

Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects

¹Department of Biology and ²School of Kinesiology and Health Science, York University, Toronto M3J 1P3; and ³The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8

Submitted 9 May 2003 ; accepted in final form 26 November 2003

Defects in mitochondrial DNA (mtDNA) evoke distinctive responses in the nuclear genome, leading to altered mitochondrial biogenesis. We used C₂C₁₂ cells depleted of mtDNA (rho^– cells) and fibroblasts from a mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) patient to examine adaptations of the protein import machinery and transcription factors involved in mitochondrial biogenesis. In rho^– cells, Tom20 and Tim23 protein levels were reduced by 25% and 59%, whereas mtHSP70 was induced by twofold 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%, whereas Tom20 and Tom34 protein levels were increased by 45% and 112% relative to control values. EYFP import was not altered in MELAS cells. In rho^– cells, protein levels of the transcription factors nuclear respiratory factor-1 (NRF-1) and transcription factor A (Tfam) declined by 33% and 54%, whereas no change was observed for the coactivator peroxisome proliferator receptor- coactivator-1 (PGC-1). In contrast, Tfam was increased by 40% in MELAS cells. Rho^– cells displayed reduced oxygen consumption (O₂) and ATP levels, along with a twofold increase in lactate levels (P < 0.05). In electrically stimulated C₂C₁₂ cells, 109%, 78%, 60%, and 67% increases were observed in mtDNA, O₂, cytochrome-c oxidase (COX) activity, and Tom34 levels, respectively (P < 0.05). Our findings suggest that compensatory adaptations occurred to maintain normal rates of protein import in response to mtDNA defects and support a role for contractile activity in reducing pathophysiology associated with mtDNA depletion. Because the expression of nuclear-encoded transcription factors and protein import machinery components was dependent on the type of mtDNA defect, these findings suggest involvement of distinct signaling cascades, each dependent on the type of mitochondrial defect, resulting in divergent changes in nuclear gene expression patterns.

mitochondrial biogenesis; skeletal muscle; rho^– cells; mitochondrial disease; peroxisome proliferator-activated receptor- coactivator-1

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