bims-algemi 2020-03-15 papers

Issue of 2020‒03‒15
two papers selected by
Atif Towheed
Columbia University Irving Medical Center

Mol Genet Genomic Med. 2020 Mar 12. e1199

Systematic analysis of a mitochondrial disease-causing ND6 mutation in mitochondrial deficiency.

Deyu Chen, Qiongya Zhao, Jingting Xiong, Xiaoting Lou, Qinxia Han, Xiujuan Wei, Jie Xie, Xueyun Li, Huaibin Zhou, Lijun Shen, Yanling Yang, Hezhi Fang, Jianxin Lyu.

BACKGROUND: The m.14487T>C mutation is recognized as a diagnostic mutation of mitochondrial disease during the past 16 years, emerging evidence suggests that mutant loads of m.14487T>C and disease phenotype are not closely correlated.METHODS: Immortalized lymphocytes were generated by coculturing the Epstein-Barr virus and lymphocytes from m.14487T>C carrier Chinese patient with Leigh syndrome. Fifteen cytoplasmic hybrid (cybrid) cell lines were generated by fusing mtDNA lacking 143B cells with platelets donated by patients. Mitochondrial function was systematically analyzed at transcriptomic, metabolomic, and biochemical levels.
RESULTS: Unlike previous reports, we found that the assembly of mitochondrial respiratory chain complexes, mitochondrial respiration, and mitochondrial OXPHOS function was barely affected in cybrid cells carrying homoplastic m.14487T>C mutation. Mitochondrial dysfunction associated transcriptomic and metabolomic reprogramming were not detected in cybrid carrying homoplastic m.14487T>C. However, we found that mitochondrial function was impaired in patient-derived immortalized lymphocytes.
CONCLUSION: Our data revealed that m.14487T>C mutation is insufficient to cause mitochondrial deficiency; additional modifier genes may be involved in m.14487T>C-associated mitochondrial disease. Our results further demonstrated that a caution should be taken by solely use of m.14487T>C mutation for molecular diagnosis of mitochondrial disease.

Keywords: cybrids; mitochondrial disease; mtDNA mutation; transcriptome and metabolic analyses

DOI: https://doi.org/10.1002/mgg3.1199

Free Radic Biol Med. 2020 Mar 08. pii: S0891-5849(19)32344-5. [Epub ahead of print]

Mitochondrial superoxide/hydrogen peroxide: An emerging therapeutic target for metabolic diseases.

Jialong Yan, Jinyong Jiang, Lu He, Linxi Chen.

Mitochondria are well known for their roles as energy and metabolic factory. Mitochondrial reactive oxygen species (mtROS) refer to superoxide anion radical (•O2-) and hydrogen peroxide (H2O2). They are byproducts of electron transport in mitochondrial respiratory chain and are implicated in the regulation of physiological and pathological signal transduction. Especially when mitochondrial •O2-/H2O2 production is disturbed, this disturbance is closely related to the occurrence and development of metabolic diseases. In this review, the sources of mitochondrial •O2-/H2O2 as well as mitochondrial antioxidant mechanisms are summarized. Furthermore, we particularly emphasize the essential role of mitochondrial •O2-/H2O2 in metabolic diseases. Specifically, perturbed mitochondrial •O2-/H2O2 regulation aggravates the progression of metabolic diseases, including diabetes, gout and nonalcoholic fatty liver disease (NAFLD). Given the deleterious effect of mitochondrial •O2-/H2O2 in the development of metabolic diseases, antioxidants targeting mitochondrial •O2-/H2O2 might be an attractive therapeutic approach for the prevention and treatment of metabolic diseases.

Keywords: Antioxidants; Diabetes; Gout; Mitochondrial (•)O(2)(−)/H(2)O(2); NAFLD

DOI: https://doi.org/10.1016/j.freeradbiomed.2020.02.029