Interplay of Mitochondrial Biogenesis and Oxidative Stress in Heart Failure Running title: Cooper; Role of mitochondrial biogenesis in heart failure

f iversity of Ma as s ssac ac a hu hu huse se sett tt tts s s 2 The dawn of mitochondrially powered cells began 1-2 billion years ago when an amitochonriate host subsumed Į-Proteobacterium, a hydrogen-producing symbiont 1. Equipped to oxidize nutrients, eurkaryotic cells acquired a 'boost' to cellular energy, enabling the emergence of multi-cellular mammals, sustained by a nearly inexhaustible muscular pump— the heart. In this issue of Circulation, MacLellan and colleagues 2 examine interplay of mitochondria biogenesis and oxidative stress in human cardiomyopathy. They reveal that disparate changes in mitochondrial biogenesis and mitochondrial oxidative stress distinguish between ischemic cardiomyopathy and dilated cardiomyopathy. Using a complement of ultrastructural, biochemical and genetic analyses, MacLellan and colleagues convincingly show that mitochondrial content is increased in dilated cardiomyopathic (DCM) hearts (n= 8) but not ischemic cardiomyopathic (ICM) hearts (n= 8). Irrespective of heart failure etiology, oxidative phosphorylation (OXPHOS) was severely impaired, a finding universally reported by others. Given that mitochondrial content was increased about 2-fold in DCM hearts, these data may imply better maintenance of total cellular OXPHOS in DCM hearts compared with ICM hearts. Because mitochondrial mass is influenced by proliferation (mitochondrial biogenesis) and clearance (mitophagy), the authors investigated the mechanistic basis for increased mitochondrial content in DCM hearts. Notably, PGC-1a (PPARGC1a), a potent regulator of mitochondrial biogenesis 3 , as well as several target genes of PGC-1Į were induced at the level of mRNA and protein in DCM hearts but not in ICM hearts. These genetic data replicate a previously reported study 4. Even so, this topic is not immune to controversy or the Proteus phenomenon, as findings by others oppugn the conclusions of MacLellan and colleagues. Using a mixed cohort, one study showed that PGC-1Į, which promotes mitochondrial biogenesis, was reduced in both ICM and DCM hearts 5. Induction of adenine colleagues convincingly show that mitochondrial content is incr t eased in dilated c c car rd di d om om omyo yo yopa pa p th thic DCM) hearts (n= 8) but not ischemic cardiomyopathic (ICM) hearts (n= 8). 3 nucleotide translocator (SLC25A4), a gene whose induction signifies mitochondrial biogenesis, was reported by Wallace and colleagues in ICM hearts (but not DCM hearts) 6 , implying mitochondrial biogenesis is specific to ICM. Similar disparities are found throughout the literature, some of which are mentioned in the work by MacLellan and colleagues. What then accounts for these …