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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Mitochondrial diseases due to mutations of nuclear DNA genes show typical autosomal or X-linked inheritance patterns and are not maternally inherited. On the other hand, mitochondrial diseases due to mutations of mtDNA show maternal inheritance, as well as wide variation in severity due to heteroplasmy. Maternal inheritance of mtDNA mitochondrial diseases occurs because essentially all mitochondria are inherited from the mother via the fertilized egg. However, the mother may be more mildly affected or even asymptomatic than the patient, even though she carries the same mtDNA mutation. This is because each mitochondrion has its own copy of mtDNA, and each cell contains hundreds of mitochondria. Therefore, any particular cell contains a mixture of normal and affected mitochondria, which is referred to as heteroplasmy. The overall ratio determines the severity of the phenotype, and it differs between each tissue within the body. This can lead to unexpected results on genetic testing because, for example, a patient with very severe neurological symptoms due to a high ratio of mutant mitochondria in the brain may have blood genetic testing that only shows a few abnormal mitochondria in white blood cells.
Role of Mitochondrial Dysfunction in Human Obesity
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
David Albuquerque, Sara Carmo-Silva, Daniel Álvarez-Vaca, Célia Aveleira, Clévio Nóbrega
This small spherical organelle is present in each cell with thousand copies and holds its own genome. The human mitochondrial genome possesses a maternal inheritance and have been used in several kinds of studies including, maternal family ties, Eva mitochondrial, etc. (Vigilant et al., 1991; Howell et al. 2000). Several mutations have been also identified associated with diverse forms of human diseases (Taylor and Turnbull, 2005).
Reproductive Approaches to Prevent the Transmission of Mitochondrial Diseases
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
María Jesús Sánchez-Calabuig, Noelia Fonseca Balvís, Serafín Pérez-Cerezales, Pablo Bermejo-Álvarez
Mitochondria are small endosymbiotic organelles that function using genes encoded by their own circular genomes (mtDNA) as well as from nuclear DNA (nDNA). The dual origin of the DNA sequences (mtDNA or nDNA) required for proper functioning entails two possible causes of inheritable mitochondrial diseases: nDNA mutations or mtDNA mutations. The inheritable mitochondrial diseases, caused by mutations in nDNA, follow essentially the same Mendelian patterns of inheritance than any other inheritable disease caused by alterations in the chromosomic DNA sequence (Houstek et al. 2004). However, mitochondrial diseases caused by mtDNA mutations are subjected to two major differential features of mtDNA which contradicts Mendelian rules: (1) the exclusive maternal inheritance and (2) the presence of multiple copies of mtDNA per cell, which determines that most mitochondrial diseases occur in heteroplasmy (i.e., the coexistence of two populations of mutant and wild type mtDNA).
Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Abraham J. Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch
The mitochondrial metabolism is probably the most intricate within cellular metabolism. The double genetic origin that controls oxidative phosphorylation (OXPHOS), in which proteins are codified by either nuclear or mitochondrial genomes (mitochondria are the only organelles with such double genetic regulation), and the fundamental pathways that occur in mitochondria partially explain this complexity [1,2]. All clinical presentations, ages of disease onset and inheritance types (e.g. maternal, X-linked, dominant, recessive, or sporadic) are possible in mitochondrial diseases (MDs), which are a group of rare genetic disorders that impair different mitochondrial biological functions [2,3]. When mutations are detected in nuclear genes (nDNA), they follow Mendelian inheritance and exhibit dominant, recessive or X-linked patterns. However, when mutations are localized in mitochondrial DNA (mtDNA), maternal inheritance, or sporadic mutations occur along with other genetic features such as heteroplasmy, mitotic segregation, or random distributions of mutated mtDNA among cells. Thus, the pathophysiological mechanisms of MDs are heterogeneous, and the diagnostic and treatment monitoring aspects present challenges to health professionals and researchers working in this field [3–5]. This group includes clinical laboratory professionals, because the lack of specificity and sensitivity of the currently available biomarkers used in clinical laboratories for both diagnostic and patient follow-up purposes is generally recognized [6–8].
The epidemiology and mutation types of Leber’s hereditary optic neuropathy in Thailand
Published in Annals of Medicine, 2022
Kanchalika Sathianvichitr, Benjaporn Sigkaman, Niphon Chirapapaisan, Poramaet Laowanapiban, Tanyatuth Padungkiatsagul, Supanut Apinyawasisuk, Juthamat Witthayaweerasak, Wanicha Chuenkongkaew
In recent years, genetic testing has played a crucial role in LHON diagnosis. The testing focuses on three common mutations, G11778A, T14484C, and G3460A, which account for more than 95% of cases [6]. These missense mutations occur in mitochondrial DNA (mtDNA). They code a subunit of the respiratory chain complex I, leading to free radical accumulation and cell apoptosis [6]. Another positive attribute of genetic testing is its prognostic capability. While the G11778A mutation produces the most severe visual loss with the poorest recovery, the visual loss caused by T14484C has the best chance of recovery. In contrast to other mitochondrial diseases, maternal inheritance in LHON patients manifest incomplete penetration and a male predominance. The reasons for this are not well established. Several studies [7–9] proposed that environmental factors such as smoking and alcohol consumption, hormonal factors and genetic modifiers including secondary mutations and haplogroup status are involved.
Yiqi Huoxue Tongluo recipe regulates NR4A1 to improve renal mitochondrial function in unilateral ureteral obstruction (UUO) rats
Published in Pharmaceutical Biology, 2022
Zhen He, Mengjuan Zhang, Hepeng Xu, Wenping Zhou, Chang Xu, Zheng Wang, Ming He, Xiangting Wang
The mitochondrion is a small organelle exclusively of maternal inheritance and is directly involved in many essential cellular functions, including generating ATP through the tricarboxylic acid (TCA) cycle and mitochondrial electron transport chain (ETC)-mediated oxidative phosphorylation (OXPHOS) to meet the energy required for cell survival, promoting growth and metabolism (Wallace 1999; Newmeyer and Ferguson-Miller 2003). The kidney has the second highest mitochondrial content and oxygen consumption after the heart. In the kidney, proximal tubules require abundant mitochondria to provide sufficient energy for ATP, which required for tubular reabsorption and secretion, and are highly dependent on OXPHOS (Weinberg et al. 2000). Therefore, the kidneys are exquisitely dependent on mitochondria and are susceptible to mitochondrial damage (Che et al. 2014). Evidence indicates that mitochondrial dysfunction is not only an early event in kidney injury but also contributes to the development and progression of CKD (Sivitz and Yorek 2010; Sharma et al. 2013). Mitochondrial dysfunction leads to proteinuria increase (Su et al. 2013), NLRP3 inflammasome activation (Gong et al. 2016), uraemic toxin stagnation (Gewin et al. 2017), and transforming growth factor-β (TGF-β) expression (Casalena et al. 2012). Mitochondria are becoming a popular topic in CKD treatment, and the exploration of renal tubular mitochondrial function in CKD might provide an effective treatment strategy for CKD.