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.

We have reported previously that hearts from type 2 diabetic ( db/ db) mice show decreased cardiac efficiency due to increased work-independent myocardial O₂ consumption (unloaded MV̇o₂), indicating higher O₂ use for nonmechanical processes such as basal metabolism (MV̇o_2BM) and excitation-contraction coupling (MV̇o_2ECC). Although alterations in cardiac metabolism and/or Ca²⁺ handling may contribute to increased energy expenditure in diabetic hearts, direct measurements of the O₂ cost for these individual processes have not been determined. In this study, we 1) validate a procedure for measuring unloaded MV̇o₂ directly (MV̇o_2unloaded) and for determining MV̇o_2BM and MV̇o_2ECC separately in isolated perfused mouse hearts and 2) determine O₂ cost for these processes in hearts from db/ db mice. Unloaded MV̇o₂, extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and MV̇o₂, was found to correspond with MV̇o₂ measured directly in unloaded retrograde perfused hearts (MV̇o_2unloaded). MV̇o₂ in K⁺-arrested hearts was defined as MV̇o_2BM; the difference between MV̇o_2unloaded and MV̇o_2BM represented MV̇o_2ECC. This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca²⁺ concentrations resulted in changes in either MV̇o_2BM and/or MV̇o_2ECC. The higher MV̇o_2unloaded in db/ db mice was due to both a higher MV̇o_2BM and MV̇o_2ECC. Elevation of glucose and insulin decreased FA oxidation and reduced both MV̇o_2unloaded and MV̇o_2BM. In conclusion, this study provides direct evidence that MV̇o_2BM and MV̇o_2ECC are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a MV̇o₂-lowering effect.

The aim of the present study was to evaluate the underlying processes involved in the oxygen wasting induced by inotropic drugs and acute and chronic elevation of fatty acid (FA) supply, using unloaded perfused mouse hearts from normal and type 2 diabetic ( db/db) mice. We found that an acute elevation of the FA supply in normal hearts, as well as a chronic (in vivo) exposure to elevated FA as in db/db hearts, increased myocardial oxygen consumption (MV̇o_2unloaded) due to increased oxygen cost for basal metabolism and for excitation-contraction (EC) coupling. Isoproterenol stimulation, on top of a high FA supply, led to an additive increase in MV̇o_2unloaded, because of a further increase in oxygen cost for EC coupling. In db/db hearts, the acute elevation of FA did not further increase MV̇o₂. Since the elevation in the FA supply is accompanied by increased rates of myocardial FA oxidation, the present study compared MV̇o₂following increased FA load versus FA oxidation rate by exposing normal hearts to normal and high FA concentration (NF and HF, respectively) and to compounds that either stimulate (GW-610742) or inhibit [dichloroacetate (DCA)] FA oxidation. While HF and NF + GW-610742 increased FA oxidation to the same extent, only HF increased MV̇o_2unloaded. Although DCA counteracted the HF-induced increase in FA oxidation, DCA did not reduce MV̇o_2unloaded. Thus, in normal hearts, acute FA-induced oxygen waste is 1) due to an increase in the oxygen cost for both basal metabolism and EC coupling and 2) not dependent on the myocardial FA oxidation rate per se, but on processes initiated by the presence of FAs. In diabetic hearts, chronic exposure to elevated circulating FAs leads to adaptations that afford protection against the detrimental effect of an acute FA load, suggesting different underlying mechanisms behind the increased MV̇o₂following acute and chronic FA load.

An acute myocardial fat-load leads to oxidative stress, oxygen wasting, mechanical inefficiency, hyperacetylation, and impaired mitochondrial function, which can contribute to reduced ischemic tolerance. Following obesity/insulin resistance, hearts were less affected by a high fat-load, which subsequently also improved ischemic tolerance. This study highlights that an acute fat-load affects normal and obese hearts differently and that obesity renders hearts less vulnerable to the disadvantageous effects of an acute fat-load.

Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO₂) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIO_WT) and global NOK2 knock-out mice (DIO_KO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIO_APO). Mitochondrial function and ROS production were also assessed in DIO and DIO_APO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO₂ for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.

The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII₅₀ and AngII₄₀₀) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII₅₀ caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII₄₀₀ slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII₄₀₀ induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.