Stimulation of mitochondrial gene expression and proliferation of mitochondria following impairment of cellular energy transfer by inhibition of the phosphocreatine circuit in rat hearts.
Mitochondria proliferate when cellular energy demand increases. However, the pathways leading to enhanced expression of mitochondrial genes are largely unknown. We tested the hypothesis that an altered flux through energy metabolism is the key regulatory event by decreasing mitochondrial energy supply to rat heart cells by creatine depletion. Electron microscopy showed that the density of mitochondria increased by 75% in such hearts (p < 0.01). Levels of representative mRNAs encoded on mitochondrial DNA (mtDNA) or on nuclear chromosomes were elevated 1.5 to 2-fold (p < 0.05), while the mtDNA content was unchanged. The mRNA for the nuclear encoded mitochondrial transcription factor A (mtTFA) was increased after GPA feeding (p < 0.05). Thus, we have shown that an impairment of mitochondrial energy supply causes stimulation of gene expression resulting in mitochondrial proliferation, probably as a compensatory mechanism. The observed activation of the mtTFA gene corroborates the important function of this protein in nuclear-mitochondrial communication.
Wiesner
R J
RJ
Department of Physiology II, University of Heidelberg, Germany. Rudolf.Wiesner@uni-koeln.de
Hornung
T V
TV
Garman
J D
JD
Clayton
D A
DA
O'Gorman
E
E
Wallimann
T
T
D000818:Animals; D015152:Blotting, Northern; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D004735:Energy Transfer / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D010725:Phosphocreatine / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000096:biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D029867:Xenopus Proteins
D004272:DNA, Mitochondrial; D006146:Guanidines; D011422:Propionates; D012333:RNA, Messenger; D015534:Trans-Activators; C097078:XL-MTTFA protein, Xenopus; D029867:Xenopus Proteins; D010725:Phosphocreatine; D003576:Electron Transport Complex IV; C005775:guanidinopropionic acid