Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy

Abstract

Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.

Successful transcatheter mitral valve repair for functional mitral regurgitation in a patient with mitochondrial cardiomyopathy: a case report

“…Mitochondrial diseases are caused by genetic mutations in nuclear DNA or mtDNA that impair oxidative phosphorylation, ultimately resulting in the dysfunction of multiple organs, including the brain, muscles, heart, and those in the endocrine system. 1 , 2 In general, mitochondrial diseases caused by nuclear DNA are more common because nuclear DNA is inherited from both parents, leading to early symptom manifestation. In contrast, the clinical features of mitochondrial disease caused by mtDNA mutation vary owing to differences in the proportions of normal and mutated mtDNA among cells and organs; this is called heteroplasmy.…”

“…Mitochondrial diseases are a group of genetic disorders caused by nuclear or mitochondrial DNA (mtDNA) gene mutations. 1 , 2 The A to G mtDNA point mutation at position 3243 (m.3243A>G) is the most common mtDNA mutation; it is found in ∼60% of mitochondrial disease cases and involved in multiorgan disorders, including cardiomyopathy. 3 The most common pathology of mitochondrial cardiomyopathy (MCM) with m.3243A>G is hypertrophic cardiopathy (HCM).…”

Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases

“…Mitochondrial cardiomyopathies are structural or functional abnormalities of the myocardium caused by defects in nuclear DNA or mtDNA genes and are usually characterized by hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects [ 80 ]. Potential treatments are to transplant or deliver entirely new mitochondria from healthy cells to diseased cells to improve outcomes in patients with acquired or congenital mitochondrial defects due to mitochondrial mutations [ 44 ].…”

Cryopreservation: A Comprehensive Overview, Challenges, and Future Perspectives

“…Recent advances in the and biological composition results in different outputs for the cryopreservation process based on different methods for thawing. [8,10,11] This allows the cryopreservation process to be segmented into multiple linked aspects to be monitored and resolve the technical obstacles. In this context, container choice, amount of cryoprotectants (CPAs), mode of cooling and vitrification process (formation of noncrystalline substance into glass), storage conditions, thawing procedure, and viability assessment, are critical elements that need to be addressed.…”

“…Scientists have coined the term "cryogenicists" for the ones who are concerned with such studies in the field of cryobiology. [11,12] All these need to be controlled individually and collectively for effective cryopreservation and the quality of the final product. Alternatively, ice crystallization can be minimized, that is by rapid cooling into the glass state thus eliminating structural damage due to freezing.…”