Mitochondrial influences on smooth muscle phenotype

Abstract

Smooth muscle cells transition reversibly between contractile and noncontractile phenotypes in response to diverse influences, including many from mitochondria. Numerous molecules including myocardin, procontractile miRNAs, and the mitochondrial protein prohibitin-2 promote contractile differentiation; this is opposed by mitochondrial reactive oxygen species (mtROS), high lactate concentrations, and metabolic reprogramming induced by mitophagy and/or mitochondrial fission. A major pathway through which vascular pathologies such as oncogenic transformation, pulmonary hypertension, and atherosclerosis cause loss of vascular contractility is by enhancing mitophagy and mitochondrial fission with secondary effects on smooth muscle phenotype. Proproliferative miRNAs and the mitochondrial translocase TOMM40 also attenuate contractile differentiation. Hypoxia can initiate loss of contractility by enhancing mtROS and lactate production while simultaneously depressing mitochondrial respiration. Mitochondria can reduce cytosolic calcium by moving it across the inner mitochondrial membrane via the mitochondrial calcium uniporter, and then through mitochondria-associated membranes to and from calcium stores in the sarcoplasmic/endoplasmic reticulum. Through these effects on calcium, mitochondria can influence multiple calcium-sensitive nuclear transcription factors and genes, some of which govern smooth muscle phenotype, and possibly also the production of genomically encoded mitochondrial proteins and miRNAs (mitoMirs) that target the mitochondria. In turn, mitochondria also can influence nuclear transcription and mRNA processing through mitochondrial retrograde signaling, which is currently a topic of intensive investigation. Mitochondria also can signal to adjacent cells by contributing to the content of exosomes. Considering these and other mechanisms, it is becoming increasingly clear that mitochondria contribute significantly to the regulation of smooth muscle phenotype and differentiation.

Keywords: metabolic reprogramming; mitoMirs; mitochondria-associated membranes; mitochondrial calcium; mitochondrial retrograde signaling.

Graphical abstract

Figure 1.

Mitochondrial influences on smooth muscle phenotype. This figure summarizes recent evidence that mitochondria influence smooth muscle phenotype. Please note that smooth muscle cells exhibit a broad and complex continuum of independently regulated phenotypic characteristics; smooth muscle phenotype is diagrammed here as two main phenotypic families for diagrammatic simplicity. Mitochondria influence smooth muscle phenotype and differentiation through at least four main categories of mechanisms. First, mitochondrial dynamics, including the processes of fission, fusion, biogenesis and mitophagy, regulate the number, size, and distribution of mitochondria within smooth muscle cells. In turn, these characteristics can induce metabolic reprogramming that potently promotes contractile dedifferentiation. Changes in mitochondrial dynamics are strongly influenced by many pathological processes including oncogenic and atherosclerotic transformation and the development of pulmonary hypertension. Second, mitochondrial ROS production promotes inflammation and strongly promotes contractile dedifferentiation and conversion into an osteochrondrocytic phenotype that mediates vascular calcification. The production of mtROS is enhanced by hypoxia but attenuated by SOD2, which is abundant within mitochondria. Third, the mitochondrial calcium uniporter (MCU) can facilitate uptake and release of calcium, which can significantly influence local cytosolic calcium concentration, affect rates of nuclear calcium uptake, and thereby influence calcium-sensitive gene transcription. Mitochondrial calcium can stimulate respiration, alter mitochondrial dynamics and ROS production, and influence the movement of calcium between the mitochondrial interior and adjacent sarcoplasmic/endoplasmic reticulum through specialized mitochondria-associated membranes (MAMs). Fourth, mitochondria can influence rates of nuclear gene transcription through mitochondrial retrograde signaling; the molecules that mediate this signaling are largely unidentified but under intensive investigation. Conversely, the nucleus codes for a broad variety of proteins and miRNAs (mitoMirs) that traffic to the mitochondria and influence mitochondrial characteristics. Other nuclear transcripts code for molecules such as myocardin and miRNA molecules that can either promote (miRNAc) or attenuate (miRNAp) contractile differentiation and may be influenced by mitochondrial retrograde signaling. Mitochondria also release multiple proteins that can directly promote (Prohibitin-2) or retard (TOMM40) contractile differentiation. Overall, mitochondria can exert both direct and indirect influences on smooth muscle phenotype and differentiation that, in turn, may contribute to either homeostatic or pathophysiological processes. From this perspective, mitochondria can be damaged by vascular disease, but conversely also can help initiate pathophysiological processes that precipitate vascular disease.