The deactive form of respiratory complex I from mammalian mitochondria is a Na+/H+ antiporter.

In mitochondria, complex I (NADH:ubiquinone oxidoreductase) uses the redox potential energy from NADH oxidation by ubiquinone to transport protons across the inner membrane, contributing to the proton-motive force. However, in some prokaryotes, complex I may transport sodium ions instead, and three subunits in the membrane domain of complex I are closely related to subunits from the Mrp family of Na(+)/H(+) antiporters. Here, we define the relationship between complex I from Bos taurus heart mitochondria, a close model for the human enzyme, and sodium ion transport across the mitochondrial inner membrane. In accord with current consensus, we exclude the possibility of redox-coupled Na(+) transport by B. taurus complex I. Instead, we show that the "deactive" form of complex I, which is formed spontaneously when enzyme turnover is precluded by lack of substrates, is a Na(+)/H(+) antiporter. The antiporter activity is abolished upon reactivation by the addition of substrates and by the complex I inhibitor rotenone. It is specific for Na(+) over K(+), and it is not exhibited by complex I from the yeast Yarrowia lipolytica, which thus has a less extensive deactive transition. We propose that the functional connection between the redox and transporter modules of complex I is broken in the deactive state, allowing the transport module to assert its independent properties. The deactive state of complex I is formed during hypoxia, when respiratory chain turnover is slowed, and may contribute to determining the outcome of ischemia-reperfusion injury.