Modulation of the conformational state of mitochondrial complex I as a target for therapeutic intervention

Abstract

In recent years, there have been significant advances in our understanding of the functions of mitochondrial complex I other than the generation of energy. These include its role in generation of reactive oxygen species, involvement in the hypoxic tissue response and its possible regulation by nitric oxide (NO) metabolites. In this review, we will focus on the hypoxic conformational change of this mitochondrial enzyme, the so-called active/deactive transition. This conformational change is physiological and relevant to the understanding of certain pathological conditions including, in the cardiovascular system, ischaemia/reperfusion (I/R) damage. We will discuss how complex I can be affected by NO metabolites and will outline some potential mitochondria-targeted therapies in I/R damage.

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

“…Transition from the active form to the deactivated form occurs spontaneously when the supply of enzyme substrates (e.g., NADH and ubiquinone) are low, and it can be slowly reactivated as the substrates become available again. Although, the physiological role of this “active-deactivated” conversion remains unclear, it has been postulated that it is an adaptive metabolic response mechanism to variations in substrate supply [64]. …”

“…NO can directly inhibit mitochondrial respiration through S-nitrosylation of critical thiol(s) in complex I [64–66]. Interestingly, S-nitrosylation-dependent inhibition of complex I occurs only when its conformational state is in the deactivated form [67].…”

Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states

“…The dominant class of ovine complex I11 corresponds to class 3 (partially dissociated), whereas the porcine12 and human13 respirasome complexes resemble the class 2 (active) state21. In the absence of substrates, mammalian complex I relaxes from the ‘active’ state, which is resting but ready to catalyze, into a profound resting state called the ‘deactive’ state22–25. The ubiquinone-binding site in the deactive enzyme is partially disordered10,21, so the slow reactivation process that returns the enzyme to the active state upon addition of NADH and ubiquinone may be initiated by the site reforming around the ubiquinone substrate as it binds and is reduced21.…”

Structure of the Deactive State of Mammalian Respiratory Complex I

“…The “active-deactive” transition of mammalian complex I has recently come to prominence as a physiologically relevant mechanism of regulation. In the absence of substrates, complex I relaxes into a profound resting state, known as the deactive state, that can be reactivated by addition of NADH and ubiquinone ( Babot et al., 2014a , Galkin and Moncada, 2017 , Kotlyar and Vinogradov, 1990 , Vinogradov, 1998 ). Notably, because the respiratory chain cannot catalyze in the absence of O 2 (lack of an electron acceptor prevents electron flux along the chain), ischemia promotes complex I deactivation ( Galkin et al., 2009 , Maklashina et al., 2002 , Maklashina et al., 2004 ).…”