<scp>MFN2</scp>: Shaping mitochondria and cardiac adaptations to hypoxia

Abstract

In the current issue of this journal, Zhang and colleagues provide evidence on the role of the mitochondrial fusion factor mitofusin-2 (MFN2) in the regulation of cardiometabolic adaptation in mice exposed to prolonged hypobaric hypoxia (HH), corresponding to a terrestrial altitude of 5500 m.1 They demonstrate that downregulation of MFN2 preserves myocardial function by promoting cardiac metabolic reprogramming in HH, identifying MFN2 as a novel negative regulator of high-altitude adaptations.1 Hypoxia can be a result of ambient conditions, such as reduced barometric pressure and partial pressure of oxygen, as occurring at high altitude (HH), or of reduced oxygen concentrations in the inspired air. Mitochondria are the primary cellular oxygen consumers and energy producers and are therefore particularly vulnerable to hypoxia and so are organs with high energy demand, like the heart. To manage hypoxia, cells, tissues, and organisms rely on sophisticated responses, resulting in physiological adaptation or (pathological) maladaptation. The metabolic plasticity of the mammalian heart is of vital importance to preserve structure and functioning in extreme environmental conditions, including HH. MFN2 is a multifunctional protein located on the outer mitochondrial membrane, abundant in cardiac cells, and involved in diverse biological processes, from the regulation of metabolic efficiency, apoptosis and cell repair to differentiation and proliferation. It is an integral component of the molecular machinery mediating the structural organization of mitochondria, including mitochondrial fusion and physical interaction with other organelles, especially the endoplasmic reticulum. The regulation of mitochondrial shape/dynamics and mitochondrial mass (biogenesis and degradation) are essential mechanisms to ensure maintenance of mitochondrial homeostasis and quality control.2 Mitochondrial dynamics depend on mitochondrial fission and fusion, changing the shape and thereby the metabolic capacity of mitochondria. Mitochondrial-shape regulating proteins notably include the fission factor dynamin-related protein 1 (DRP1), the inner mitochondrial membrane fusion factor optic atrophy 1 (OPA1) and MFN1 and 2, which are required for outer mitochondrial membrane fusion. Hypoxia (in combination with reperfusion) modulates mitochondrial shape, in a hypoxic-dose- and cell-type-dependent manner (Figure 1A). This can result in aberrant fusion events, resulting in “donut-shaped” mitochondria or mega-mitochondria, possibly protecting from hypoxia-reperfusion events and/or regulating mitochondrial degradation.3 Conversely, activation of a major coordinator of molecular responses to hypoxia, hypoxia-inducible factor 1 (HIF1), can also induce mitochondrial fragmentation via DRP1, as shown for example in arterial smooth muscle cells.4 As Zhang and colleagues outline, both long-lasting up- and downregulation of mitochondrial fusion in the heart have been linked to beneficial or detrimental outcomes.1 While MFN2 overexpression may attenuate cardiac hypertrophy and dysfunction in heart disease, the same research group recently demonstrated that MFN2 upregulation in acute hypoxia (in mice) caused myocardial dysfunction (impaired contractility of cardiomyocytes and elevated risk of QT prolongation).5 Consequently, in the present study they hypothesized that MFN2 knockout would improve metabolic adjustment and cardiac function in HH.1 They confirmed increased MFN2 protein levels in the left and right ventricle after exposure of mice to HH (5500 m) for 4 weeks, expectedly causing elongated mitochondria. Levels of other mitochondrial shape-changing proteins (OPA1, MFN1, and DRP1) did not change. The authors again observed several detrimental consequences of HH on cardiac function (Figure 1B). In line with their hypothesis, cardiac-specific MFN2 knockout rescued many of these consequences in mice exposed to HH, notably decreased ATP levels, cardiac hypertrophy, interstitial fibrosis, and specific echocardiographic parameters.1 In cardiomyocytes cultured in 1% oxygen, siRNA-mediated knockdown of MFN2 further rescued contractility. The benefits of MFN2 deficiency were reversed by upregulation of MFN2 or reducing mitochondrial fission by inhibition of DRP1. The reason that low MFN2 levels preserved cardiac function in HH in this study likely was MFN2 knockout-related metabolic remodeling.1 Significantly reduced levels of intermediates of the oxygen-dependent tricarboxylic acid (TCA) cycle and fatty acid β oxidation were found in cardiac-specific MFN2-deficient mice, while markers of glycolysis were upregulated. This suggests that a metabolic switch to oxygen-independent energy metabolism pathways is facilitated in the absence of MFN2. While elongated mitochondria with high oxidative phosphorylation capacity in control mice likely were limited by the low oxygen availability to produce ATP, MFN2 deficiency promoted a switch to glycolysis that allowed sufficient ATP generation also in hypoxia. This hypothesis fits well with the results of a recent study on the role of MFN2 in regenerating muscle6; in this study, MFN2 was identified as a negative regulator of HIF-1. HIF-1 is essential for hypoxia adaptations, also because it coordinates upregulation of glycolysis and downregulation of oxidative phosphorylation.7 Based on the provided evidence by Zhang et al.,1 it seems plausible that MFN2 in response to hypoxia-related energetic crisis is upregulated to improve oxidative phosphorylation efficiency. While this may be an effective strategy for transient hypoxic periods, it represents a maladaptation, if the hypoxia persists. As novel insights usually do, this study not only provides answers but also raises a wide range of new questions, most importantly related to the risks of long-lasting reduction of cardiac MFN2: while likely protective in prolonged HH, it probably increases the vulnerability to several cardiac diseases and specifically impairs a switch back to oxidative energy production, in case of re-oxygenation. This may be particularly relevant for applications of mild intermittent hypoxia, in which metabolic adaptations are thought to increase cellular function and resilience.7 Although this study is highly informative regarding cardiac consequences of MFN2 deficiency in HH, it merely scratches the surface of the mechanistic underpinnings. In particular MFN2's role in mitochondrial calcium regulation deserves future investigation and also the role of hyperfusion following MFN2 upregulation in HH. The results of the current study1 indicate an unexpectedly increased mitochondrial area besides mitochondrial elongation, suggesting that quality mechanisms by mitochondrial degradation may fail. Moreover, whether MFN2 is similarly regulated by hypoxia in all tissues and how this—or specific cardiac MFN2 knockout—affects adaptation in other organ systems remains to be elucidated. Taken together, Zhang et al.1 provide intriguing evidence that the mitochondrial fusion factor MFN2 mediates unfavorable cardiac adaptive responses to HH, a finding with high physiological and clinical relevance in high-altitude and aerospace research. Martin Burtscher and Johannes Burtscher contributed equally to this work. None. There is no conflict of interest to declare.

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