Abstract
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.
Highlights
Mitochondria are dynamic, double-membrane-bound organelles that reside in all eukaryotic cells with a prominent role in metabolism, ion homeostasis and cell death.They exert essential anabolic and catabolic functions and produce ATP through oxidative phosphorylation, while mitochondrial outer membrane permeabilization, regulated by Bcl-2 family proteins, induces the intrinsic apoptotic pathway
Numerous pathogenic mutations in nuclear-encoded mitochondrial proteins have been identified that often cause neuromuscular disorders. This is exemplified by proteases, which reside in different mitochondrial compartments and preserve the functional integrity of mitochondria [1, 2]
The synthesis and intramitochondrial transport of phospholipids and the dynamic behavior of mitochondrial membranes that constantly fuse and divide are under proteolytic control
Summary
Mitochondria are dynamic, double-membrane-bound organelles that reside in all eukaryotic cells with a prominent role in metabolism, ion homeostasis and cell death They exert essential anabolic and catabolic functions and produce ATP through oxidative phosphorylation, while mitochondrial outer membrane permeabilization, regulated by Bcl-2 family proteins, induces the intrinsic apoptotic pathway. Numerous pathogenic mutations in nuclear-encoded mitochondrial proteins have been identified that often cause neuromuscular disorders This is exemplified by proteases, which reside in different mitochondrial compartments and preserve the functional integrity of mitochondria [1, 2]. AAA proteases constitute a family of conserved and ubiquitous ATP-dependent proteases that are embedded in the mitochondrial inner membrane Subunits of these hexameric proteolytic complexes harbor an ATPase domain of the AAA family (ATPases associated with diverse cellular activities) and a metallopeptidase of the M48 family. The chaperone-like activity of AAA domains ensures the specific recognition of misfolded,
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