Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice

Zhuo Li, Yanyan Peng, Robert B. Hufnagel, Yueh Chiang Hu, Chuntao Zhao, Luis F. Queme, Zaza Khuchua, Ashley M. Driver, Fei Dong, Q. Richard Lu, Diana M. Lindquist, Michael P. Jankowski, Rolf W. Stottmann, Winston W.Y. Kao, Taosheng Huang

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Recently, we identified biallelic mutations of SLC25A46 in patients withmultiple neuropathies. Functional studies revealed that SLC25A46may play an important role in mitochondrial dynamics bymediating mitochondrial fission. However, the cellular basis and pathogenic mechanismof the SLC25A46-related neuropathies are not fully understood. Thus, we generated a Slc25a46 knock-outmouse model. Mice lacking SLC25A46 displayed severe ataxia, mainly caused by degeneration of Purkinje cells. Increased numbers of small, unmyelinated and degenerated optic nerves as well as loss of retinal ganglion cells indicated optic atrophy. Compound muscle action potentials in peripheral nerves showed peripheral neuropathy associated with degeneration and demyelination in axons. Mutant cerebellar neurons have largemitochondria, which exhibit abnormal distribution and transport. Biochemically mutant mice showed impaired electron transport chain activity and accumulated autophagymarkers. Our results suggest that loss of SLC25A46 causes degeneration in neurons by affectingmitochondrial dynamics and energy production.

Original languageEnglish (US)
Pages (from-to)3776-3791
Number of pages16
JournalHuman molecular genetics
Volume26
Issue number19
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Li, Z., Peng, Y., Hufnagel, R. B., Hu, Y. C., Zhao, C., Queme, L. F., Khuchua, Z., Driver, A. M., Dong, F., Richard Lu, Q., Lindquist, D. M., Jankowski, M. P., Stottmann, R. W., Kao, W. W. Y., & Huang, T. (2017). Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice. Human molecular genetics, 26(19), 3776-3791. https://doi.org/10.1093/hmg/ddx262