Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient mdx Mice

Dubinin, Mikhail V.; Starinets, Vlada S.; Talanov, Eugeny Yu.; Mikheeva, I. B.; Belosludtseva, Natalia V.; Serov, Dmitriy A.; Tenkov, Kirill S.; Belosludtseva, Evgeniya V; Belosludtsev, Konstantin N.

doi:10.3390/biomedicines9091232

Cited by 13 publications

(11 citation statements)

References 44 publications

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“…Loss of dystrophin destabilizes the myofiber membrane to cause pathological calcium overload in the cytosol during physical activity (Bonilla et al , 1988 ; Mareedu et al , 2021 ). Cytosolic calcium overload leads to an excessive uptake of calcium by the mitochondria resulting in mitochondrial depolarization and permeability transition (Moore et al , 2020 ; Budzinska et al , 2021 ; Dubinin et al , 2021 ). While ATP depletion has been documented in mdx mice and in DMD patients (Kelly‐Worden & Thomas, 2014 ; Budzinska et al , 2021 ), the contribution of ATP hydrolysis by CV has not been tested.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies

et al. 2023

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The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV.

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Section: Resultsmentioning

confidence: 99%

Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies

et al. 2023

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“…Similar mitochondrial fragmentation was also found in a zebrafish model for DMD. Finally, Dubinin et al [ 45 ] reported that mitochondria from mdx mice were spherical structures with an irregular organization of mitochondrial cristae, and some mitochondria contained vacuoles and abnormalities in the outer membrane.…”

Section: Discussionmentioning

confidence: 99%

Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients

Willi¹,

Abramovich

Fernández-García

et al. 2022

IJMS

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Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. We tested the hypothesis that DCM is caused by metabolic impairments by employing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from four DMD patients; an adult male, an adult female, a 7-year-old (7y) male and a 13-year-old (13y) male, all compared to two healthy volunteers. To test the hypothesis, we measured the bioenergetics, metabolomics, electrophysiology, mitochondrial morphology and mitochondrial activity of CMs, using respirometry, LC–MS, patch clamp, electron microscopy (EM) and confocal microscopy methods. We found that: (1) adult DMD CMs exhibited impaired energy metabolism and abnormal mitochondrial structure and function. (2) The 7y CMs demonstrated arrhythmia-free spontaneous firing along with “healthy-like” metabolic status, normal mitochondrial morphology and activity. In contrast, the 13y CMs were mildly arrhythmogenic and showed adult DMD-like bioenergetics deficiencies. (3) In DMD adult CMs, mitochondrial activities were attenuated by 45–48%, whereas the 7y CM activity was similar to that of healthy CMs. (4) In DMD CMs, but not in 7y CMs, there was a 75% decrease in the mitochondrial ATP production rate compared to healthy iPSC-CMs. In summary, DMD iPSC-CMs exhibit bioenergetic and metabolic impairments that are associated with rhythm disturbances corresponding to the patient’s phenotype, thereby constituting novel targets for alleviating cardiomyopathy in DMD patients.

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“…Importantly, the cardiac mitochondria of mdx mice also showed an increase in the level of NCLX and the rate of release of calcium ions from the organelles in exchange for Na + (Figure 2) [171]. Activation of calcium transport in the heart mitochondria of young mdx mice is also accompanied by an increase in the intensity of oxidative phosphorylation [171,175], which, as we suggest, may determine the adaptation of the heart to an increase in the level of calcium in cardiomyocytes and delay cardiac pathology. It is possible that similar reprogramming is also observed in cardiomyocytes of DMD patients showing signs of metabolic adaptation [176], but this issue needs to be studied.…”

Section: Mitochondrial Ion Channels In Dmdmentioning

confidence: 98%

Ion Channels of the Sarcolemma and Intracellular Organelles in Duchenne Muscular Dystrophy: A Role in the Dysregulation of Ion Homeostasis and a Possible Target for Therapy

Dubinin

Belosludtsev

2023

IJMS

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Duchenne muscular dystrophy (DMD) is caused by the absence of the dystrophin protein and a properly functioning dystrophin-associated protein complex (DAPC) in muscle cells. DAPC components act as molecular scaffolds coordinating the assembly of various signaling molecules including ion channels. DMD shows a significant change in the functioning of the ion channels of the sarcolemma and intracellular organelles and, above all, the sarcoplasmic reticulum and mitochondria regulating ion homeostasis, which is necessary for the correct excitation and relaxation of muscles. This review is devoted to the analysis of current data on changes in the structure, functioning, and regulation of the activity of ion channels in striated muscles in DMD and their contribution to the disruption of muscle function and the development of pathology. We note the prospects of therapy based on targeting the channels of the sarcolemma and organelles for the correction and alleviation of pathology, and the problems that arise in the interpretation of data obtained on model dystrophin-deficient objects.

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Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient mdx Mice

Cited by 13 publications

References 44 publications

Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies

Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies

Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients

Ion Channels of the Sarcolemma and Intracellular Organelles in Duchenne Muscular Dystrophy: A Role in the Dysregulation of Ion Homeostasis and a Possible Target for Therapy

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