Mitochondrial dysfunction in cardiac ischemia-reperfusion injury: ROS from complex I, without inhibition.

Departments of Anesthesiology, and Biochemistry & Molecular Biology, Box 604, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester NY 14642, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 03/2006; 1762(2):223-31. DOI: 10.1016/j.bbadis.2005.10.001
Source: PubMed

ABSTRACT A key pathologic event in cardiac ischemia reperfusion (I-R) injury is mitochondrial energetic dysfunction, and several studies have attributed this to complex I (CxI) inhibition. In isolated perfused rat hearts, following I-R, we found that CxI-linked respiration was inhibited, but isolated CxI enzymatic activity was not. Using the mitochondrial thiol probe iodobutyl-triphenylphosphonium in conjunction with proteomic tools, thiol modifications were identified in several subunits of the matrix-facing 1alpha sub-complex of CxI. These thiol modifications were accompanied by enhanced ROS generation from CxI, but not complex III. Implications for the pathology of cardiac I-R injury are discussed.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumour necrosis factor (TNF)-α has been considered to induce ischaemia-reperfusion injury (IRI) of liver which is characterized by energy dysmetabolism. Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α and mitofusion2 (Mfn2) are reported to be involved in the regulation of mitochondrial function. However, whether PGC-1α and Mfn2 form a pathway that mediates liver IRI, and if so, what the underlying involvement is in that pathway remain unclear. In this study, L02 cells administered recombinant human TNF-α had increased TNF-α levels and resulted in down-regulation of PGC-1α and Mfn2 in a rat liver IRI model. This was associated with hepatic mitochondrial swelling, decreased adenosine triphosphate (ATP) production, and increased levels of reactive oxygen species (ROS) and alanine aminotransferase (ALT) activity as well as cell apoptosis. Inhibition of TNF-α by neutralizing antibody reversed PGC-1α and Mfn2 expression, and decreased hepatic injury and cell apoptosis both in cell culture and in animals. Treatment by rosiglitazone sustained PGC-1α and Mfn2 expression both in IR livers, and L02 cells treated with TNF-α as indicated by increased hepatic mitochondrial integrity and ATP production, reduced ROS and ALT activity as well as decreased cell apoptosis. Overexpression of Mfn2 by lentiviral-Mfn2 transfection decreased hepatic injury in IR livers and L02 cells treated with TNF-α. However, there was no up-regulation of PGC-1α. These findings suggest that PGC-1α and Mfn2 constitute a regulatory pathway, and play a critical role in TNF-α-induced hepatic IRI. Inhibition of the TNF-α or PGC-1α/Mfn2 pathways may represent novel therapeutic interventions for hepatic IRI.
    Journal of Cellular and Molecular Medicine 06/2014; DOI:10.1111/jcmm.12320 · 3.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (-)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated. Methods and results: Ischemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 week reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 h and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1 h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2+ load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation. Conclusions: IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.
    International Journal of Cardiology 05/2014; 175(2). DOI:10.1016/j.ijcard.2014.05.009 · 6.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Simple multicellular animal model systems are central to studying the complex mechanisms underlying a bewildering array of diseases involving dysfunctional mitochondria. Mutant nuclear- and mitochondrial-encoded subunits of the Caenorhabditis elegans mitochondrial respiratory chain (MRC) have been investigated, including GAS-1, NUO-1, NUO-6, MEV-1, SDHB-1, CLK-1, ISP-1, CTB-1, and ATP-2. These, as well as proteins that modify the MRC indirectly, have been studied on the molecular, cellular, and organismal levels through the variety of experimental approaches that are readily achievable in C. elegans. In C. elegans, MRC dysfunction can mimic signs and symptoms observed in human patients with primary mitochondrial disorders, such as neuromuscular deficits, developmental delay, altered anesthetic sensitivity, and increased lactate levels. Antioxidant dietary supplements, coenzyme Q substitutes, and flavin cofactors have been explored as potential therapeutic strategies. Furthermore, mutants with altered longevity have proved useful for probing the contributions of bioenergetics, reactive oxygen species, and stress responses to the process of aging. C. elegans will undoubtedly continue to provide a useful system in which to explore unanswered questions in mitochondrial biology and disease.

Full-text (2 Sources)

Available from
Mar 3, 2015