Intracellular to Interorgan Mitochondrial Communication in Striated Muscle in Health and Disease

Abstract

Mitochondria sense both biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling organelles are recognized as key for regulating different cell functions. This review summarizes recent advances in mitochondrial communication in striated muscle, with specific focus on the processes by which mitochondria communicate with each other, other organelles, and across distant organ systems. Intermitochondrial communication in striated muscle is mediated via conduction of the mitochondrial membrane potential to adjacent mitochondria, physical interactions, mitochondrial fusion or fission, and via nanotunnels, allowing for the exchange of proteins, mitochondrial DNA, nucleotides, and peptides. Within striated muscle cells, mitochondria-organelle communication can modulate overall cell function. The various mechanisms by which mitochondria communicate mitochondrial fitness to the rest of the body suggest that extracellular mitochondrial signaling is key during health and disease. Whereas mitochondria-derived vesicles might excrete mitochondria-derived endocrine compounds, stimulation of mitochondrial stress can lead to the release of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) into the circulation to modulate whole-body physiology. Circulating mitochondrial DNA are well-known alarmins that trigger the immune system and may help to explain low-grade inflammation in various chronic diseases. Impaired mitochondrial function and communication are central in common heart and skeletal muscle pathologies, including cardiomyopathies, insulin resistance, and sarcopenia. Lastly, important new advances in research in mitochondrial endocrinology, communication, medical horizons, and translational aspects are discussed.

Keywords: FGF21; GDF15; mitochondria-organelle interactions; mitochondrial cristae; mitochondrial dynamics; myokines; respiratory supercomplexes.

Graphical Abstract

Figure 1.

Mitochondrial distribution in skeletal and cardiac muscle. Due to physical constraints within the muscle fibers, intrafibrillar mitochondria of striated muscle undergo a lower rate of dynamics and can communicate through direct intermitochondrial interaction. A) Schematic view of striated muscle fiber organization. Skeletal muscle fibers are polynucleated and juxtaposed, while cardiomyocytes are mononucleated and branched. B) Electron microscopy images showing the “grid-like” mitochondrial distribution (in dark) in striated muscle fibers.

Figure 2.

Schematic representation of intermitochondrial communication. A) Mitochondrial fusion, nanotunnels, and intermitochondrial junctions (IMJ) promote intermitochondrial communication and exchange of proton-motive force, mtDNA, and mitochondrial proteins. Optic atrophy 1 (OPA1) and Mitofusin 1/2 (MFN1/2) are the main proteins involved in the mitochondrial fusion process. B) Magnification of mitochondrial cristae organization. The mitochondrial contact site and cristae organizing system (MICOS), ATP synthase, and OPA1 determine the cristae shape. The mitochondrial respiratory complexes, localized in the inner mitochondrial membrane (IMM), may also communicate through formation of supercomplexes that dynamically adapt to the metabolic requirements within the cell.

Figure 3.

The physiological relevance of mitochondrial-organelle communication. Intracellular mitochondria-organelle communication is mediated by direct membrane contact sites, the exchange of metabolites, redox state, as well as through mitochondrial-derived vesicles. Whereas mitochondria-sarcoplasmic reticulum interaction is required for calcium-dependent energy metabolism and mitochondria-peroxisome communication regulates lipid metabolism and peroxisomal biogenesis, these mitochondria-organelle interactions also contribute to redox balance and respiratory supercomplex assembly. In turn, fatty acid oxidation is modulated by the metabolic interplay between mitochondria and lipid droplets. Mitochondrial biogenesis and apoptosis can dictate cell fate and are regulated by mitochondrial-nucleus crosstalk. Reactive oxygen species (ROS) play important signaling roles, in addition to altered ATP levels, calcium accumulation, triggering mitochondrial unfolded protein response (mtUPR), the integrated stress response and mitonuclear retrograde signaling. Various stressors, including ROS, stimulate the release of mitochondrial-derived vesicles, and the delivery of mitochondrial cargo to the lysosomes for degradation.

Figure 4.

Endocrine communication of mitochondrial stress–derived FGF21 and GDF15 to maintain whole-body homeostasis and metabolism. A) Autocrine/paracrine effects of FGF21 and GDF15 include muscle fiber size reduction and increased insulin sensitivity in skeletal muscle, while in the heart, FGF21 and GDF15 induce glucose uptake and are associated with cardioprotective effects. B) When muscle-derived FGF21 and GDF15 are systemically released, they induce several effects in distant organs, such as white adipose tissue (WAT) browning. C) FGF21 and GDF15 respond to mitochondrial stress by inducing a mitohormetic dual-dose response. A low dose of stress stimuli promotes health and lifespan by activating local adaptive responses to increase stress resistance and systemic effects, improving whole-body metabolism. Conversely, higher stress stimuli can lead to adverse outcomes, suggesting a failure in the myomitokines capacity to exert homeostatic compensatory mechanisms that protect against the insult. Question marks indicate that it is still unknown how the peripheral GDF15 effects are mediated since the only GDF15 receptor identified so far is the GFRAL receptor localized in the hindbrain. The cardiac contribution of FGF21 and GDF15 to the general circulation has not been demonstrated to date.