Functional Mechanisms of Mitochondrial Respiratory Chain Supercomplex Assembly Factors and Their Involvement in Muscle Quality

Abstract

Impairment of skeletal muscle function causes disabilities in elderly people. Therefore, in an aged society, prevention and treatment of sarcopenia are important for expanding healthy life expectancy. In addition to aging, adipose tissue disfunction and inflammation also contribute to the pathogenesis of sarcopenia by causing the combined state called 'sarcopenic obesity'. Muscle quality as well as muscle mass contributes to muscle strength and physical performance. Mitochondria in the skeletal muscles affect muscle quality by regulating the production of energy and reactive oxygen species. A certain portion of the mitochondrial respiratory chain complexes form a higher-order structure called a "supercomplex", which plays important roles in efficient energy production, stabilization of respiratory chain complex I, and prevention of reactive oxygen species (ROS) generation. Several molecules including phospholipids, proteins, and certain chemicals are known to promote or stabilize mitochondrial respiratory chain supercomplex assembly directly or indirectly. In this article, we review the distinct mechanisms underlying the promotion or stabilization of mitochondrial respiratory chain supercomplex assembly by supercomplex assembly factors. Further, we introduce regulatory pathways of mitochondrial respiratory chain supercomplex assembly and discuss the roles of supercomplex assembly factors and regulatory pathways in skeletal muscles and adipose tissues, believing that this will lead to discovery of potential targets for prevention and treatment of muscle disorders such as sarcopenia.

Keywords: adipose tissue; mitochondria; respiratory chain supercomplex; sarcopenia; skeletal muscle.

Figure 1

Molecules involved in mitochondrial respiratory chain supercomplex assembly. The respiratory chain supercomplex assembly factors and molecules affecting supercomplex formation which are reported to function in mitochondria of vertebrates are shown. Cardiolipin (CL), a phospholipid with four acyl chains, directly binds respiratory chain complexes on the cardiolipin binding sites in each complex. Cardiolipin may indirectly support mitochondrial respiratory chain supercomplex formation by maintaining cristae structure. COX7RP (cytochrome c oxidase subunit 7a-related polypeptide; also known as COX7A2L/SCAF1), HIGD2A (HIG1 hypoxia inducible domain family, member 2A), and UQCC3 (ubiquinol-cytochrome c reductase complex assembly factor 3) function as bridging proteins by direct binding with each respiratory chain complex. PHB1 (prohibitin 1), PHB2 (prohibitin 2), and SLP2 (stomatin-like protein 2) are SPFH (stomatin, prohibitin, flotillin, and Hflk/C) proteins which inhibit activity of proteases, mAAA (a member of AAA (ATPase associated with diverse cellular activities) proteins with enzymatic sites in the matrix of mitochondria) and iAAA (a member of AAA proteins with enzymatic sites in the intermembrane space of mitochondria), causing degradation of OPA1 (optic atrophy 1) responsible for the maintenance of cristae structure. Five bioactive small molecules are also shown. Coenzyme Q10 and melatonin are antioxidants that protect cardiolipin from reactive oxygen species (ROS). Functions of melatonin are also mediated by its G-protein coupled receptors (MT1 and MT2) or by nuclear receptor ROR (retinoid acid receptor-related orphan receptor). Nobiletin also activates ROR. T3 type of thyroid hormone binds to thyroid hormone receptor (TR). TR forms heterodimer with retinoid X receptor (RXR). T3 increases the amount of cardiolipin. Elamipretide is a synthetic tetrapeptide which modulates electrostatics of the mitochondrial inner membrane.

Figure 2

Putative mechanisms of mitochondrial respiratory chain supercomplex formation by exercise. Exercise intervention was shown to induce respiratory chain supercomplex formation [86]. Four putative regulatory mechanisms of respiratory chain supercomplex formation in skeletal muscle by exercise are shown. Exercise increases oxygen and glucose consumption, and induces secretion of myokines called ‘exerkines’. Hypoxia induces expression of HIGD2A (HIG1 hypoxia inducible domain family, member 2A), while insufficient glucose induces expression of COX7RP (cytochrome c oxidase subunit 7a-related polypeptide) through endoplasmic reticulum (ER) stress. Interleukin-15 (IL-15) is an exerkine which promotes mitochondrial respiratory chain supercomplex with an unknown mechanism. Routine exercise is shown to increase expression of OPA1 (optic atrophy 1) in skeletal muscles.