Mitochondrial abnormalities have long been described in the setting of cardiomyopathies and heart failure (HF), yet the mechanisms of mitochondrial dysfunction in cardiac pathophysiology remain poorly understood. Many studies have described HF as an energy-deprived state characterized by a decline in adenosine triphosphate production, largely driven by impaired oxidative phosphorylation. However, impairments in oxidative phosphorylation extend beyond a simple decline in adenosine triphosphate production and, in fact, reflect pervasive metabolic aberrations that cannot be fully appreciated from the isolated, often siloed, interrogation of individual aspects of mitochondrial function. With the application of broader and deeper examinations into mitochondrial and metabolic systems, recent data suggest that HF with preserved ejection fraction is likely metabolically disparate from HF with reduced ejection fraction. In our review, we introduce the concept of the mitochondrial ecosystem, comprising intricate systems of metabolic pathways and dynamic changes in mitochondrial networks and subcellular locations. The mitochondrial ecosystem exists in a delicate balance, and perturbations in one component often have a ripple effect, influencing both upstream and downstream cellular pathways with effects enhanced by mitochondrial genetic variation. Expanding and deepening our vantage of the mitochondrial ecosystem in HF is critical to identifying consistent metabolic perturbations to develop therapeutics aimed at preventing and improving outcomes in HF.

Recent trends suggest novel natural compounds as promising treatments for cardiovascular disease. The authors examined how neopetroside A, a natural pyridine nucleoside containing an α-glycoside bond, regulates mitochondrial metabolism and heart function and investigated its cardioprotective role against ischemia/reperfusion injury. Neopetroside A treatment maintained cardiac hemodynamic status and mitochondrial respiration capacity and significantly prevented cardiac fibrosis in murine models. These effects can be attributed to preserved cellular and mitochondrial function caused by the inhibition of glycogen synthase kinase-3 beta, which regulates the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide, reduced, through activation of the nuclear factor erythroid 2-related factor 2/NAD(P)H quinone oxidoreductase 1 axis in a phosphorylation-independent manner.

Muscular atrophy (MA) is a disease of various origins, i.e., genetic or the most common, caused by mechanical injury. So far, there is no universal therapeutic model because this disease is often progressive with numerous manifested symptoms. Moreover, there is no safe and low-risk therapy dedicated to muscle atrophy. For this reason, our research focuses on finding an alternative method using natural compounds to treat MA. This study proposes implementing natural substances such as celastrol and Rhynchophylline on the cellular level, using a simulated and controlled atrophy process. Methods: Celastrol and Rhynchophylline were used as natural compounds against simulated atrophy in C2C12 cells. Skeletal muscle C2C12 cells were stimulated for the differentiation process. Atrophic conditions were obtained by the exposure to the low concertation of doxorubicin and validated by FoxO3 and MAFbx. The protective and regenerative effect of drugs on cell proliferation was determined by the MTT assay and MT-CO1, VDAC1, and prohibitin expression. Results: The obtained results revealed that both natural substances reduced atrophic symptoms. Rhynchophylline and celastrol attenuated atrophic cells in the viability studies, morphology analysis by diameter measurements, modulated prohibitin VDAC, and MT-CO1 expression. Conclusions: The obtained results revealed that celastrol and Rhynchophylline could be effectively used as a supportive treatment in atrophy-related disorders. Thus, natural drugs seem promising for muscle regeneration.

UNASSIGNED: Tourniquet-induced ischemia and reperfusion (I/R) has been related to postoperative muscle atrophy through mechanisms involving protein synthesis/breakdown, cellular metabolism, mitochondrial dysfunction, and apoptosis. Ischemic preconditioning (IPC) could protect skeletal muscle against I/R injury. This study aims to determine the underlying mechanisms of IPC and its effect on muscle strength after total knee arthroplasty (TKA).
UNASSIGNED: Twenty-four TKA patients were randomized to receive either sham IPC or IPC (3 cycles of 5-min ischemia followed by 5-min reperfusion). Vastus medialis muscle biopsies were collected at 30 ​min after tourniquet (TQ) inflation and the onset of reperfusion. Western blot analysis was performed in muscle protein for 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1ser616, Drp1, Mfn1, Mfn2, Opa1, PGC-1ɑ, ETC complex I-V, cytochrome c, cleaved caspase-3, and caspase-3. Clinical outcomes including isokinetic muscle strength and quality of life were evaluated pre- and postoperatively.
UNASSIGNED: IPC significantly increased Mfn2 (2.0 ​± ​0.2 vs 1.2 ​± ​0.1, p ​= ​0.001) and Opa1 (2.9 ​± ​0.3 vs 1.9 ​± ​0.2, p ​= ​0.005) proteins expression at the onset of reperfusion, compared to the ischemic phase. There were no differences in 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1ser616/Drp1, Mfn1, PGC-1ɑ, ETC complex I-V, cytochrome c, and cleaved caspase-3/caspase-3 expression between the ischemic and reperfusion periods, or between the groups. Clinically, postoperative peak torque for knee extension significantly reduced in the sham IPC group (-16.6 [-29.5, -3.6] N.m, p ​= ​0.020), while that in the IPC group was preserved (-4.7 [-25.3, 16.0] N.m, p ​= ​0.617).
UNASSIGNED: In TKA with TQ application, IPC preserved postoperative quadriceps strength and prevented TQ-induced I/R injury partly by enhancing mitochondrial fusion proteins in the skeletal muscle.
UNASSIGNED: Mitochondrial fusion is a potential underlying mechanism of IPC in preventing skeletal muscle I/R injury. IPC applied before TQ-induced I/R preserved postoperative quadriceps muscle strength after TKA.

Mitochondrial Ca2+ overload contributes to obesity cardiomyopathy, yet mechanisms that directly regulate it remain elusive. The authors investigated the role of Parkin on obesity-induced cardiac remodeling and dysfunction in human hearts and a mouse model of 24-week high-fat diet (HFD) feeding. Parkin knockout aggravated HFD-induced cardiac remodeling and dysfunction, mitochondrial Ca2+ overload, and apoptosis without affecting global metabolism, blood pressure, and aortic stiffness. Parkin deficiency unmasked HFD-induced decline in voltage-dependent anion channel (VDAC) type 1 degradation through the ubiquitin-proteasome system but not other VDAC isoforms or mitochondrial Ca2+ uniporter complex. These data suggest that Parkin-mediated proteolysis of VDAC type 1 is a promising therapeutic target for obesity cardiomyopathy.

The burden of heart failure (HF) in terms of health care expenditures, hospitalizations, and mortality is substantial and growing. The failing heart has been described as \"energy-deprived\" and mitochondrial dysfunction is a driving force associated with this energy supply-demand imbalance. Existing HF therapies provide symptomatic and longevity benefit by reducing cardiac workload through heart rate reduction and reduction of preload and afterload but do not address the underlying causes of abnormal myocardial energetic nor directly target mitochondrial abnormalities. Numerous studies in animal models of HF as well as myocardial tissue from explanted failed human hearts have shown that the failing heart manifests abnormalities of mitochondrial structure, dynamics, and function that lead to a marked increase in the formation of damaging reactive oxygen species and a marked reduction in on demand adenosine triphosphate synthesis. Correcting mitochondrial dysfunction therefore offers considerable potential as a new therapeutic approach to improve overall cardiac function, quality of life, and survival for patients with HF.

Severe inborn cardiac malformations are typically corrected in cardioplegia, with a cardio-pulmonary bypass (CPB) taking over body circulation. During the operation the arrested hearts are subjected to a global ischemia/reperfusion injury. Although the applied cardioplegic solutions have a certain protective effect, application of additional substances to reduce cardiac damage are of interest.18 domestic piglets (10-15 kg) were subjected to a 90 min CPB and a 120 min reperfusion phase without or with the application of epigallocatechin-3-gallate (10 mg/kg body weight) or minocycline (4 mg/kg body weight), with both drugs given before and after CPB. 18 additional sham-operated piglets without or with epigallocatechin-3-gallate or minocycline served as controls. In total 36 piglets were analyzed (3 CPB-groups and 3 control groups without or with epigallocatechin-3-gallate or minocycline respectively; 6 piglets per group). Hemodynamic and blood parameters and ATP-measurements were assessed. Moreover, a histological evaluation of the heart muscle was performed.
UNASSIGNED: Piglets of the CPB-group needed more catecholamine support to achieve sufficient blood pressure. Ejection fraction and cardiac output were not different between the 6 groups. However, cardiac ATP-levels and blood lactate were significantly lower and creatine kinase was significantly higher in the three CPB-groups. Markers of apoptosis, hypoxia, nitrosative and oxidative stress were significantly elevated in hearts of the CPB-group. Nevertheless, addition of epigallocatechin-3-gallate or minocycline significantly reduced markers of myocardial damage. Noteworthy, EGCG was more effective in reducing markers of hypoxia, whereas minocycline more efficiently decreased inflammation.
UNASSIGNED: While epigallocatechin-3-gallate or minocycline did not improve cardiac hemodynamics, markers of myocardial damage were significantly lower in the CPB-groups with epigallocatechin-3-gallate or minocycline supplementation.

Despite therapeutic advances, acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. One potential limitation of the current treatment paradigm is the lack of effective therapies to optimize reperfusion after ischemia and prevent reperfusion-mediated injury. Experimental studies indicate that this process accounts for up to 50% of the final infarct size, lending it importance as a potential target for cardioprotection. However, multiple therapeutic approaches have shown potential in pre-clinical and early phase trials but a paucity of clear clinical benefit when expanded to larger studies. Here we explore this history of trials and errors of the studies of cyclosporine A and other mitochondrial membrane permeability inhibitors, agents that appeared to have a promising pre-clinical record yet provided disappointing results in phase III clinical trials.

Deregulated metabolism is gaining recognition as a hallmark of cancer cells, and is being explored for therapeutic potential. The Warburg effect is a metabolic phenotype that occurs in 90% of tumors, where glycolysis is favored despite the presence of oxygen. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor that can reverse the Warburg effect. PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) is a novel anti-mitochondrial agent that targets the adenine nucleotide transporter in mitochondria and is currently in clinical trials for solid tumors. We have investigated the targeting of two aspects of metabolism, using DCA to promote mitochondrial activity combined with PENAO to inhibit mitochondrial activity, in breast and other carcinoma cell lines. PENAO was effective at low uM concentrations in luminal (T-47D) and triple negative (MDA-MB-231) breast cancer cells, in normoxia and hypoxia. The cytotoxicity of PENAO was enhanced by DCA by a mechanism involving increased reactive oxygen species in both T-47D and MDA-MB-231 cells, however further investigations found it did not always involve PDK2 inhibition or reduction of the mitochondrial membrane potential, which are the accepted mechanisms for DCA induction of apoptosis. Nevertheless, DCA sensitized all cancer cell lines tested toward apoptosis of PENAO. DCA and PENAO are both currently in clinical trials and targeting cancer metabolism with these drugs may offer options for difficult to treat cancers.

Insulin resistance is associated with mitochondrial dysfunction, but the mechanism by which mitochondria inhibit insulin-stimulated glucose uptake into the cytoplasm is unclear. The mitochondrial permeability transition pore (mPTP) is a protein complex that facilitates the exchange of molecules between the mitochondrial matrix and cytoplasm, and opening of the mPTP occurs in response to physiological stressors that are associated with insulin resistance. In this study, we investigated whether mPTP opening provides a link between mitochondrial dysfunction and insulin resistance by inhibiting the mPTP gatekeeper protein cyclophilin D (CypD) in vivo and in vitro. Mice lacking CypD were protected from high fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. The mitochondria in CypD knockout muscle were resistant to diet-induced swelling and had improved calcium retention capacity compared to controls; however, no changes were observed in muscle oxidative damage, insulin signaling, lipotoxic lipid accumulation or mitochondrial bioenergetics. In vitro, we tested 4 models of insulin resistance that are linked to mitochondrial dysfunction in cultured skeletal muscle cells including antimycin A, C2-ceramide, ferutinin, and palmitate. In all models, we observed that pharmacological inhibition of mPTP opening with the CypD inhibitor cyclosporin A was sufficient to prevent insulin resistance at the level of insulin-stimulated GLUT4 translocation to the plasma membrane. The protective effects of mPTP inhibition on insulin sensitivity were associated with improved mitochondrial calcium retention capacity but did not involve changes in insulin signaling both in vitro and in vivo. In sum, these data place the mPTP at a critical intersection between alterations in mitochondrial function and insulin resistance in skeletal muscle.