Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism

Biochimica Et Biophysica Acta
Alfonso OyarzabalPilar Rodríguez-Pombo

Abstract

Mutations on the mitochondrial-expressed Branched Chain α-Keto acid Dehydrogenase Kinase (BCKDK) gene have been recently associated with a novel dietary-treatable form of autism. But, being a mitochondrial metabolism disease, little is known about the impact on mitochondrial performance. Here, we analyze the mitochondrial response to the BCKDK-deficiency in patient's primary fibroblasts by measuring bioenergetics, ultra-structural and dynamic parameters. A two-fold increase in superoxide anion production, together with a reduction in ATP-linked respiration and intracellular ATP levels (down to 60%) detected in mutants fibroblasts point to a general bioenergetics depletion that could affect the mitochondrial dynamics and cell fate. Ultrastructure analysis of BCKDK-deficient fibroblasts shows an increased number of elongated mitochondria, apparently associated with changes in the mediator of inner mitochondria membrane fusion, GTPase OPA1 forms, and in the outer mitochondrial membrane, mitofusin 2/MFN2. Our data support a possible hyperfusion response of BCKDK-deficient mitochondria to stress. Cellular fate also seems to be affected as these fibroblasts show an altered proportion of the cells on G0/G1 and G2/M phases. Knockdown o...Continue Reading

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Citations

Jun 9, 2016·BioResearch Open Access·Walter H MoosKosta Steliou
Sep 28, 2017·Journal of Inherited Metabolic Disease·Eric S GoetzmanRadhika H Muzumdar
Nov 7, 2019·Journal of Clinical Medicine·Irene Bravo-AlonsoPilar Rodríguez-Pombo
May 11, 2018·Oxidative Medicine and Cellular Longevity·Eva RichardLourdes R Desviat
Aug 11, 2020·Progress in Retinal and Eye Research·Meysam YazdankhahNadezda A Stepicheva

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