Investigating the role of respiratory complex I in the transition from pressure-inducedhypertrophy to heart failure by xenogeneic expression of Ndi1

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Chronically increased pressure load to the heart causes cardiac hypertrophy, which eventually leads to contractile dysfunction and heart failure. Underlying mechanisms for this transition are still a matter of debate. Mitochondrial dysfunction based upon defects in the electron transport chain (ETC) has been proposed as a key mechanism. We and others demonstrated impaired respiratory capacities, specifically related to complex I, preceding the onset of contractile dysfunction. Respiratory chain complexes are therefore an attractive treatment target. In an earlier study, we have demonstrated that bypassing a defective respiratory complex III by alternative oxidase (AOX) in mice with Gracile syndrome can prevent the development of a lethal cardiomyopathy. We here propose to use Ndi1, a single subunit NADH dehydrogenase of Saccharomyces cerevisiae, to bypass complex I in a rat model of hypertrophy and heart failure induced by transverse aortic constriction (TAC). We generated rats constitutively expressing Ndi1 specifically for this purpose. Notably, Ndi1 transfers electrons directly from NADH to ubiquinone in a non-protonmotive manner and thus decreases ETC efficiency. If oxygen and reducing equivalents are abundant, however, complexes III and IV can compensate for the loss of complex I activity. Using Ndi1, we thus expect to prevent the onset of contractile dysfunction upon pressure load induced by TAC. The proposed study therefore serves three purposes. (1) We will test an intensely debated cause of pressure-induced heart failure (i.e., a possible defect in complex I). (2) We may lay the foundations for a new therapeutic concept, i.e., a bypass of impaired respiratory complexes by alternative enzymes such as Ndi1. (3) We address an old but never proven paradigm, where a “critical heart mass” is thought to cause regional hypoxia due to increasing oxygen diffusion distances during the development of hypertrophy. Since Ndi1 activity requires abundance in oxygen, we may possibly find out whether regional hypoxia is involved in the process of heart failure development, because a lack of oxygen would not allow Ndi1 to elicit disease-mitigating effects.