Journal of internal medicine
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Nonalcoholic fatty liver disease (NAFLD) is a rising global disease associated with clinical and economic burdens. ⋯ Of 77.33 million people in the United States have NAFLD with 17.63 million having advanced fibrosis, with lowest prevalence in non-Hispanic Asians and highest in Mexican Americans. A conundrum exists amongst non-Hispanic Blacks who have low NAFLD prevalence but highest prevalence of advanced fibrosis. Awareness of NAFLD was low across all ethnicities. Effort is needed to improve disease awareness whilst addressing NAFLD clinical burden across ethnicities.
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Mitochondria play central roles in cellular energetics, metabolism and signalling. Efficient respiration, mitochondrial quality control, apoptosis and inheritance of mitochondrial DNA depend on the proper architecture of the mitochondrial membranes and a dynamic remodelling of inner membrane cristae. Defects in mitochondrial architecture can result in severe human diseases affecting predominantly the nervous system and the heart. ⋯ These protein complexes and phospholipids are embedded in a network of functional interactions. They communicate with each other and additional factors, enabling them to balance different aspects of cristae biogenesis and to dynamically remodel the inner mitochondrial membrane. Genetic alterations disturbing these membrane-shaping factors can lead to human pathologies including fatal encephalopathy, dominant optic atrophy, Leigh syndrome, Parkinson's disease and Barth syndrome.
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Mutations in the mitochondrial genome are the cause of many debilitating neuromuscular disorders. Currently, there is no cure or treatment for these diseases, and symptom management is the only relief doctors can provide. Although supplements and vitamins are commonly used in treatment, they provide little benefit to the patient and are only palliative. ⋯ This is a useful feature to take advantage of for gene therapy applications, as not every mutant copy of mtDNA needs to be eliminated, but only enough to shift the heteroplasmic ratio below the disease threshold. Several DNA-editing enzymes have been used to shift heteroplasmy in cell culture and mice. This review provides an overview of these enzymes and discusses roadblocks of applying these to gene therapy in humans.
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The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ-specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late-onset common human diseases including Parkinson's disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age-related diseases. ⋯ In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far-reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.