Mitochondrial respiratory complex I: structure, function and implication in human diseases

Abstract

Mitochondria are ubiquitous organelles in eukaryotic cells whose primary function is to generate energy supplies in the form of ATP through oxidative phosphorylation. As the entry point for most electrons into the respiratory chain, NADH:ubiquinone oxidoreductase, or complex I, is the largest and least understood component of the mitochondrial oxidative phosphorylation system. Substantial progress has been made in recent years in understanding its subunit composition, its assembly, the interaction among complex I and other respiratory components, and its role in oxidative stress and apoptosis. This review provides an updated overview of the structure of complex I, as well as its cellular functions, and discusses the implication of complex I dysfunction in various human diseases.

Fig. (1)

Structural constituents of mammalian complex I. The subunit composition of complex I encoded by nuclear and mtDNA along with known assembly proteins are shown. The nuclear-encoded 38 subunits and seven mtDNA-encoded subunits form an L-shaped structure of complex I. Numbers in parentheses signify number of subunits. Assembly proteins, proteins which have been reported to mediate complex I assembly or maintain the complex I stability.

Fig. (2)

Functionality of complex I in different cellular pathways. Signaling pathways triggered by ROS production through complex I or other sources are shown. ROS can also affect complex I to generate more free radicals. Some additional functions are suggested based on the similarity of complex I subunits to other proteins. NFkβ, nuclear factor κB; ASK1, apoptosis signal–regulating kinase 1; MAPK, mitogen-activated protein kinase; JNK, c-jun N-terminal kinase; ERK, extracellular signal–regulated kinase; PKC, protein kinase C; PI3K, phosphoinositide kinase 3; Akt, serine/threonine protein kinase; COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; pTEN, phosphatase and tensin homolog; NADH, reduced nicotinamide adenine dinucleotide; ACPs; acyl carrier proteins. Pathways involved in the direct association of complex I are in boldface type.