MITOCHONDRIAL DYNAMICS AND METABOLIC REGULATION IN CARDIAC AND SKELETAL MUSCLE

Abstract

Mitochondria are the metabolic powerhouses of cells. In addition to generating adenosine triphosphate (ATP), they play important roles in cell survival pathways such as apoptosis and necrosis. Mitochondrial size and shape are dynamically regulated by a process known as mitochondrial dynamics. The significance of this process in metabolically active cells such as skeletal and cardiac muscle are only now beginning to be elucidated. In cardiac muscle, mitochondrial dynamics plays an important role in mitochondrial quality control and defects in regulatory pathways that govern these processes and leads to heart failure. In response to nutrient excess such as lipid overload, as occurs in diabetes, mitochondrial shape and morphology are altered by effects of nutrient stress on mitochondrial dynamics signaling pathways, which have important implications for understanding mitochondrial dysfunction in diabetic cardiomyopathy. Moreover, crosstalk between mitochondria and other organelles such as the endoplasmic reticulum can regulate generation of hormones such as fibroblast growth factor 21, with potent anti-diabetic and anti-obesity effects.

Fig. 1

Schematic representation of mitochondrial structure.

Fig. 2

(A) Schematic representation of mitochondrial fusion and molecular mediators of mitochondrial outer membrane fusion (mitofusin 1/2 [MFN1/2]) and optic atrophy 1 (OPA1). (B) Schematic representation of mitochondrial fission and its molecular mediators Mitochondrial fission 1 (Fis-1) and dynamin-related protein 1 (DRP1). The schematic shows DRP1 phosphorylation on serine 637 (p-DRP1) which promotes cytosolic localization, whereas dephosphorylation increases association with fis1 to promote mitochondrial fission.

Fig. 3

Schematic representation of mechanisms by which a reduction of optic atrophy 1 (OPA1) levels in skeletal muscle leads to the activation of the endoplasmic reticulum (ER) stress pathway and induction of fibroblast growth factor 21 (FGF21) gene expression and FGF21 release. Abbreviations: ATF, Activating Transcription Factor 4; MURF, muscle ring finger protein 1; DIO, diet-induced obesity; IR, insulin resistance.

Fig. 4

(A) Two-dimensional electron micrographs of cardiac tissue from healthy hearts and from the hearts of mice with lipid overload that develops as a result of overexpression of Acyl-CoA synthetase. (B) Schematic representation of the mechanisms by which increased mitochondrial lipid overload induced by overexpression of Acyl-CoA synthetase generates reactive oxygen species (ROS) that leads to decreased phosphorylation of DRP1 and inactivation of OPA1 that ultimately results in increased mitochondrial fission. Abbreviations: OPA1, optic atrophy 1; DRP1, dynamin-related protein; ATP, adenosine triphosphate; PKA, protein kinase A; Acyl-CoA, acyl Coenzyme A synthetase; ACSL1, Acyl-CoA synthetase isoform 1; AKAP 121, A Kinase anchoring protein 121; NADH, reduced nicotinamide adenine dinucleotide.