Universität zu Köln

Patron, Maria, Sprenger, Hans-Georg and Langer, Thomas (2018). m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration. Cell Res., 28 (3). S. 296 - 307. SHANGHAI: INST BIOCHEMISTRY & CELL BIOLOGY. ISSN 1748-7838

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Patron, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprenger, Hans-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-193245
DOI:	10.1038/cr.2018.17
Journal or Publication Title:	Cell Res.
Volume:	28
Number:	3
Page Range:	S. 296 - 307
Date:	2018
Publisher:	INST BIOCHEMISTRY & CELL BIOLOGY
Place of Publication:	SHANGHAI
ISSN:	1748-7838
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEREDITARY SPASTIC PARAPLEGIA; PERMEABILITY TRANSITION PORE; DOMINANT CEREBELLAR-ATAXIA; PROTEIN-QUALITY CONTROL; CA2+ UPTAKE; CELL-SURVIVAL; MCU ACTIVITY; MUTATIONS; UNIPORTER; AFG3L2 Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19324