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Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy

Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities w...

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Autores principales: Dong, Tingting, Zhang, Zai‐Qiang, Sun, Li‐Hong, Zhang, Weilong, Zhu, Zhaohui, Lin, Lin, Yang, Lin, Lv, An, Liu, Chunying, Li, Qing, Yang, Rui‐Feng, Zhang, Xiuru, Niu, Yamei, Chen, Hou‐Zao, Liu, De‐Pei, Tong, Wei‐Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307528/
https://www.ncbi.nlm.nih.gov/pubmed/36974636
http://dx.doi.org/10.1111/bpa.13157
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author Dong, Tingting
Zhang, Zai‐Qiang
Sun, Li‐Hong
Zhang, Weilong
Zhu, Zhaohui
Lin, Lin
Yang, Lin
Lv, An
Liu, Chunying
Li, Qing
Yang, Rui‐Feng
Zhang, Xiuru
Niu, Yamei
Chen, Hou‐Zao
Liu, De‐Pei
Tong, Wei‐Min
author_facet Dong, Tingting
Zhang, Zai‐Qiang
Sun, Li‐Hong
Zhang, Weilong
Zhu, Zhaohui
Lin, Lin
Yang, Lin
Lv, An
Liu, Chunying
Li, Qing
Yang, Rui‐Feng
Zhang, Xiuru
Niu, Yamei
Chen, Hou‐Zao
Liu, De‐Pei
Tong, Wei‐Min
author_sort Dong, Tingting
collection PubMed
description Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age‐dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N‐acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo‐insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies.
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spelling pubmed-103075282023-06-30 Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy Dong, Tingting Zhang, Zai‐Qiang Sun, Li‐Hong Zhang, Weilong Zhu, Zhaohui Lin, Lin Yang, Lin Lv, An Liu, Chunying Li, Qing Yang, Rui‐Feng Zhang, Xiuru Niu, Yamei Chen, Hou‐Zao Liu, De‐Pei Tong, Wei‐Min Brain Pathol Research Articles Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age‐dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N‐acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo‐insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies. John Wiley and Sons Inc. 2023-03-28 /pmc/articles/PMC10307528/ /pubmed/36974636 http://dx.doi.org/10.1111/bpa.13157 Text en © 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Dong, Tingting
Zhang, Zai‐Qiang
Sun, Li‐Hong
Zhang, Weilong
Zhu, Zhaohui
Lin, Lin
Yang, Lin
Lv, An
Liu, Chunying
Li, Qing
Yang, Rui‐Feng
Zhang, Xiuru
Niu, Yamei
Chen, Hou‐Zao
Liu, De‐Pei
Tong, Wei‐Min
Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
title Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
title_full Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
title_fullStr Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
title_full_unstemmed Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
title_short Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
title_sort mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307528/
https://www.ncbi.nlm.nih.gov/pubmed/36974636
http://dx.doi.org/10.1111/bpa.13157
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