Abstract
Mitochondria are major contributors to ATP synthesis, generating more than 90% of the total cellular energy production through oxidative phosphorylation (OXPHOS): metabolite oxidation, such as the β-oxidation of fatty acids, and the Krebs’s cycle. OXPHOS inadequacy due to large genetic lesions in mitochondrial as well as nuclear genes and homo- or heteroplasmic point mutations in mitochondrially encoded genes is a characteristic of heterogeneous, maternally inherited genetic disorders known as mitochondrial disorders that affect multisystemic tissues and organs with high energy requirements, resulting in various signs and symptoms. Several traditional diagnostic approaches, including magnetic resonance imaging of the brain, cardiac testing, biochemical screening, variable heteroplasmy genetic testing, identifying clinical features, and skeletal muscle biopsies, are associated with increased risks, high costs, a high degree of false-positive or false-negative results, or a lack of precision, which limits their diagnostic abilities for mitochondrial disorders. Variable heteroplasmy levels, mtDNA depletion, and the identification of pathogenic variants can be detected through genetic sequencing, including the gold standard Sanger sequencing. However, sequencing can be time consuming, and Sanger sequencing can result in the missed recognition of larger structural variations such as CNVs or copy-number variations. Although each sequencing method has its own limitations, genetic sequencing can be an alternative to traditional diagnostic methods. The ever-growing roster of possible mutations has led to the development of next-generation sequencing (NGS). The enhancement of NGS methods can offer a precise diagnosis of the mitochondrial disorder within a short period at a reasonable expense for both research and clinical applications.
Highlights
Introduction to Mitochondria and Mitochondrial DisordersMitochondria are membrane-bound [1], intracellular and cytoplasmic organelles [2] that significantly contribute to oxidative energy metabolism in cells through the regulation of energy homeostasis by metabolizing nutrients to produce ATP which serves as a cellular energy source, and generate heat [3,4]
This study demonstrated that next-generation sequencing (NGS) approaches such as nWES provide a more accurate diagnosis regarding mitochondrial disorder (MD) than the traditional approaches [178]
Diverse mitochondrial disorders are associated with clinical features that can be difficult to differentiate and diagnose due to an ever-increasing number of suspected genes and complicated data analyses
Summary
Mitochondria are membrane-bound [1], intracellular and cytoplasmic organelles [2] that significantly contribute to oxidative energy metabolism in cells through the regulation of energy homeostasis by metabolizing nutrients to produce ATP which serves as a cellular energy source, and generate heat [3,4]. Mitochondrial dysfunction resulting in excess fatigue due to efficiency failure concerning the electron transport chain, reduced generation of ATP such as high-energy molecules, inadequate mitochondria number, and scarcity of necessary mitochondria substrates include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease [44,46–48] along with other neurodegenerative, cardiovascular, and autoimmune diseases [49–51]. The prevalence of these mitochondrial diseases worldwide is counted as near about one in every five thousand people expressing the maximum ordinary group of inherited metabolic disorders. We will discuss NGS technology for diagnosing mitochondrial diseases as well as the pros and cons of these techniques with respect to diagnosis
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