Alternative Oxidase as Rescue-Mechanism for Mitochondrial Dysfunction in Heart Failure
Final Report Abstract
We and others demonstrated in rats with increased cardiac afterload that the development of contractile dysfunction is associated with impaired complex I activity of the mitochondrial electron transport chain (ETC). Here, we use a rat model with xenotopic expression of Ndi1, an alternative respiratory enzyme bypassing complex I, to elucidate a mechanistic link between the development of pressure-induced contractile failure and complex I dysfunction. Weanling male Sprague-Dawley (SD) rats expressing Ndi1 and wild-type controls were subjected to increased cardiac pressure load induced by transverse aortic constriction (TAC). Survival time was documented and cardiac morphology and function were assessed by echocardiography. Expression of Ndi1 had no effect on body weight, heart rate, or cardiac morphology and function. Two weeks after TAC, wild-type rats showed impaired cardiac contractile function compared with SHAM controls. There was decreased stroke volume and heart rate, resulting in significantly decreased cardiac output. At the same time, Ndi1-expressing rats subjected to TAC maintained heart rates and stroke volumes, resulting in maintained cardiac output. Both groups showed the expected hypertrophic left ventricular walls after TAC. However, only wild-type rats showed additionally reduced left ventricular inner dimensions in diastole compared to healthy controls. Preliminary survival analyses indicate a slightly higher survival in Ndi1-expressing rats after 2 weeks of pressure overload, although statistical significance has not yet been reached. Bypassing complex I of the respiratory chain by xenotopic expression of Ndi1 maintains contractile function and may extend survival under pressure overload. If verified in a larger cohort, these results suggest a causal role for complex I dysfunction in pressure-overloadinduced heart failure.
Publications
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Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction. Mammalian Genome, 34(2), 229-243.
Spielmann, Nadine; Schenkl, Christina; Komlódi, Tímea; da Silva-Buttkus, Patricia; Heyne, Estelle; Rohde, Jana; Amarie, Oana V.; Rathkolb, Birgit; Gnaiger, Erich; Doenst, Torsten; Fuchs, Helmut; Gailus-Durner, Valérie; de Angelis, Martin Hrabě & Szibor, Marten
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Targeting the alternative oxidase (AOX) for human health and food security, a pharmaceutical and agrochemical target or a rescue mechanism?. Biochemical Journal, 479(12), 1337-1359.
Szibor, Marten; Schenkl, Christina; Barsottini, Mario R. O.; Young, Luke & Moore, Anthony L.
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The IGF-1R Inhibitor NVP-AEW541 Causes Insulin-Independent and Reversible Cardiac Contractile Dysfunction. Biomedicines, 10(8), 2022.
Schenkl, Christina; Schrepper, Andrea; Heyne, Estelle; Doenst, Torsten & Schwarzer, Michael
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Targeting Mitochondrial Metabolism to Save the Failing Heart. Life, 13(4), 1027.
Schenkl, Christina; Heyne, Estelle; Doenst, Torsten; Schulze, Paul Christian & Nguyen, Tien Dung
