m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2018,（3）
• 页码范围: 296-306
• 页数: 11页
• 语种: 英文
• DOI: 10.1038/cr.2018.17

摘要

The function of mitochondria depends on ubiquitously expressed and evolutionary conserved m-AAA proteases in the inner membrane.These ATP-dependent peptidases form hexameric complexes built up of homologous subunits.AFG3L2 subunits assemble either into homo-oligomeric isoenzymes or with SPG7 (paraplegin) subunits into hetero-oligomeric proteolytic complexes.Mutations in AFG3L2 are associated with dominant spinocerebellar ataxia (SCA28) characterized by the loss of Purkinje cells,whereas mutations in SPG7 cause a recessive form of hereditary spastic paraplegia (HSP7) with motor neurons of the cortico-spinal tract being predominantly affected.Pleiotropic functions have been assigned to m-AAA proteases,which act as quality control and regulatory enzymes in mitochondria.Loss of m-AAA proteases affects mitochondrial protein synthesis and respiration and leads to mitochondrial fragmentation and deficiencies in the axonal transport of mitochondria.Moreover m-AAA proteases regulate the assembly of the mitochondrial calcium uniporter (MCU) complex.Impaired degradation of the MCU subunit EMRE in AFG3L2-deficient mitochondria results in the formation of deregulated MCU complexes,increased mitochondrial calcium uptake and increased vulnerability of neurons for calcium-induced cell death.A reduction of calcium influx into the cytosol of Purkinje cells rescues ataxia in an AFG3L2-deficient mouse model.In this review,we discuss the relationship between the m-AAA protease and mitochondrial calcium homeostasis and its relevance for neurodegeneration and describe a novel mouse model lacking MCU specifically in Purkinje cells.Our results pledge for a novel view on m-AAA proteases that integrates their pleiotropic functions in mitochondria to explain the pathogenesis of associated neurodegenerative disorders.