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(Circulation Research. 2008;103:1191.)
© 2008 American Heart Association, Inc.

Editorials

Activation of Mitochondrial Biogenesis by Hormesis

Motoaki Sano, Keiichi Fukuda

From the Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Tokyo, Japan.

Correspondence to Motoaki Sano, Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582. E-mail msano@sc.itc.keio.ac.jp

Key Words: lipid metabolites • mitochondria • oxidative stress • redox • signaling pathways • hormesis • stress response

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Mitochondria play a major role in oxidative energy production, reduction–oxidation reaction (redox) control and calcium homeostasis. Although mitochondria contain DNA with mitochondrial-specific genes, most mitochondrial proteins are encoded by the nDNA, synthesized in the cytosol, and imported into mitochondria. The expression of nuclear genes that encode mitochondrial proteins that function in metabolic pathways such as the trichloroacetic acid cycle (TCA), oxidative phosphorylation, heme synthesis, and in mitochondrial DNA replication and transcription (eg, mitochondrial transcription factor A [Tfam]), is coordinately regulated by the transcriptional coactivators PPAR coactivator (PGC)-1 and PGC-1β through activation of nuclear respiratory factor (NRF)-1 and NRF-2.¹

In their recent publications, Piantadosi et al provided insight into the mechanisms underlying the interaction between mitochondria-derived reactive oxygen species (ROS) signaling and mitochondrial biogenesis. First, lipid hydroperoxide regulates Tfam expression through phosphorylation of NRF-1 via Akt activation, which promotes nuclear translocation of NRF-1 and binding to the Tfam promoter.² Second, carbon monoxide (CO) induced mitochondrial biogenesis via activation of Akt1/PKB and guanylate cyclase, which augmented gene and protein expression of NRF-1 and NRF-2, PGC-1, and TFAM.³ CO-induced mitochondrial ROS result in the activation of AKT. Third, the anthracycline anticancer agent doxorubicin suppresses the nuclear program for mitochondrial biogenesis, and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion and apoptosis. CO inhalation or heme oxygenase (Hmo)1 overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of AKT and guanylate cyclase.⁴ Lastly, new work in this issue of Circulation Research⁵ sheds light on the role of NF-E2–related factor . . . [Full Text of this Article]

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