A disease-associated Aifm1 variant induces severe myopathy in knockin mice

Molecular Metabolism
Lena WischhofDaniele Bano

Abstract

Mutations in the AIFM1 gene have been identified in recessive X-linked mitochondrial diseases. Functional and molecular consequences of these pathogenic AIFM1 mutations have been poorly studied in vivo. Here we provide evidence that the disease-associated apoptosis-inducing factor (AIF) deletion arginine 201 (R200 in rodents) causes pathology in knockin mice. Within a few months, posttranslational loss of the mutant AIF protein induces severe myopathy associated with a lower number of cytochrome c oxidase-positive muscle fibers. At a later stage, Aifm1 (R200 del) knockin mice manifest peripheral neuropathy, but they do not show neurodegenerative processes in the cerebellum, as observed in age-matched hypomorphic Harlequin (Hq) mutant mice. Quantitative proteomic and biochemical data highlight common molecular signatures of mitochondrial diseases, including aberrant folate-driven one-carbon metabolism and sustained Akt/mTOR signaling. Our findings indicate metabolic defects and distinct tissue-specific vulnerability due to a disease-causing AIFM1 mutation, with many pathological hallmarks that resemble those seen in patients.

Citations

Sep 17, 2020·The Journal of Cell Biology·Anjaneyulu MurariEdward Owusu-Ansah
Aug 14, 2019·Frontiers in Neurology·Carmen Fiuza-LucesMaría Morán
Jan 20, 2021·Cellular and Molecular Life Sciences : CMLS·Susanne KlausMario Ost
Nov 2, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Dafeng XuJinfang Zheng
Dec 29, 2020·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Maik HintzeThomas Franz
Feb 28, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Camille ReinhardtNazanine Modjtahedi
Apr 16, 2021·Molecular Neurodegeneration·Shuiqiao LiuYingfei Wang
Jul 3, 2021·Proteomes·David Y ChiangXander H T Wehrens

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Methods Mentioned

BETA
transfection
transgenic
PCR
electrophoresis
proteomic profiling
GTPase

Software Mentioned

ImageJ
ZEN
ImageLab
Graph Pad Prism

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis