Mammalian Mitochondrial Complex I: Biogenesis,Regulation,and Reactive Oxygen Species Generation

Abstract

Virtually every mammalian cell contains mitochondria. These double-membrane organelles continuously change shape and position and contain the complete metabolic machinery for the oxidative conversion of pyruvate, fatty acids, and amino acids into ATP. Mitochondria are crucially involved in cellular Ca²⁺ and redox homeostasis and apoptosis induction. Maintenance of mitochondrial function and integrity requires an inside-negative potential difference across the mitochondrial inner membrane. This potential is sustained by the electron-transport chain (ETC). NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest protein complex of the ETC, couples the oxidation of NADH to the reduction of ubiquinone. During this process, electrons can escape from CI and react with ambient oxygen to produce superoxide and derived reactive oxygen species (ROS). Depending on the balance between their production and removal by antioxidant systems, ROS may function as signaling molecules or induce damage to a variety of biomolecules or both. The latter ultimately leads to a loss of mitochondrial and cellular function and integrity. In this review, we discuss (a) the role of CI in mitochondrial functioning; (b) the composition, structure, and biogenesis of CI; (c) regulation of CI function; (d) the role of CI in ROS generation; and (e) adaptive responses to CI deficiency. Antioxid. Redox Signal. 12, 1431–1470.

Introduction

• Mitochondrial structure and function

• Tissue-dependent differences in electron-transport chain expression

• Composition, structure, and function of complex I

• Isolated human complex I deficiency

Biogenesis of Complex I

• Expression regulation of complex I

• Mitochondrial import of nDNA-encoded complex I subunits

• Assembly of complex I

• Supercomplex formation

• Role of mitochondrial lipids in supercomplex formation and complex I function and stability

• Proteins interacting with complex I

Complex I and Cellular ROS Generation

• Mitochondria are an important source of intracellular ROS

• Mitochondrial ROS as damaging or direct regulatory molecules or both

• Mitochondrial ROS as signaling molecules

Adaptive Responses to Complex I Deficiency

• Adaptation to rotenone-induced complex I deficiency in human skin fibroblasts

• Adaptation to mutation-induced complex I deficiency in patient fibroblasts

Conclusions