Trends in Molecular Medicine
Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia
Section snippets
Hereditary spastic paraplegia: a model disease to study dying-back axons
Neurons are highly polarized cells that form characteristic processes: the axons, which are specialized in transmitting information, and the dendrites, which are specialized in receiving and processing information. Axons are typically long processes that can project to a considerable distance from the cell body reaching lengths ≤1 m (e.g. human motor axons) and representing >99% of the total volume of the cell. Therefore, they depend on active anterograde transport for the supply of protein and
The mitochondrial m-AAA protease is involved in HSP
Mitochondria have been shown to be involved in HSP with the identification of mutations in the spastic-paraplegia-7 gene (SPG7) in families affected by a complicated form of autosomal recessive HSP [10]. Besides spastic paraparesis, some of these patients have cerebral and cerebellar atrophy and optic atrophy. SPG7 has been mapped on chromosome 16 [11] and, shortly after, it has been cloned and shown to encode a putative mitochondrial protease that is known as paraplegin. Paraplegin is highly
Proteolytic activation or complete degradation: the Janus face of the m-AAA protease
How does the loss of a ubiquitous mitochondrial protease lead to specific axonal degeneration? Given the role of the m-AAA protease in protein quality control in mitochondria, mitochondrial activities of neurons might be very sensitive towards the deleterious effect of damaged polypeptides. In an alternative but not mutually exclusive way, there might be specific substrates of the m-AAA protease, the proteolysis of which affects mitochondrial biogenesis in a tissue-specific manner. A recent
Clogged axons and enlarged mitochondria in Spg7−/− mice
What is the function of mammalian AAA proteases? Sequence conservation and successful complementation studies in yeast suggest conserved roles of the m-AAA protease in yeast and mammalian mitochondria. However, understanding the importance of the m-AAA protease in axonal degeneration and cellular pathogenesis of HSP requires an animal model of the disease; indeed, this has been generated by inactivation of Spg7 in mice [33].
Despite the shorter life span and the much shorter length of motor
Is there a link between HSP and mitochondrial translation deficiencies?
Although studies in mice provided new insight into the pathogenesis of HSP and potential therapeutic approaches, the main defect in paraplegin-deficient mitochondria, in particular the role of paraplegin in the maintenance of mitochondrial morphology, remains obscure. The dual activity of the m-AAA protease in protein processing and quality control raises the intriguing question of which function is responsible for axonal degeneration that is associated with loss of the protease. Inhibition of
Conclusion and future directions
HSP that is caused by mutations in paraplegin is currently one of the best-understood forms of HSP at the molecular level. Thanks to an exemplary crosstalk between studies in humans, mice and yeast, much has been learned on the function of paraplegin as a subunit of the mitochondrial m-AAA protease. Animal and cellular models that have been developed to study the causes of the disease and its progression are available and initial efforts towards a gene-replacement therapy have been successfully
Acknowledgements
We thank M. Nolden for help with the figures and all our colleagues for many stimulating discussions. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the German–Israeli Cooperation Project (T.L.), the European Union (6th Framework Programme) (E.I.R. and T.L.) and the Muscular Dystrophy Association and the United Mitochondrial Disease Foundation (E.I.R.).
References (76)
Motor neurons rely on motor proteins
Trends Cell Biol.
(2004)- et al.
Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias
Pharmacol. Ther.
(2006) - et al.
Is the transportation highway the right road for hereditary spastic paraplegia?
Am. J. Hum. Genet.
(2002) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease
Cell
(1998)A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3
Am. J. Hum. Genet.
(1998)AAA proteases: cellular machines for degrading membrane proteins
Trends Biochem. Sci.
(2000)The YTA10-12 complex, an AAA protease with chaperone-like activity in the inner membrane of mitochondria
Cell
(1996)Membrane protein degradation by AAA proteases in mitochondria: extraction of substrates from either membrane surface
Mol. Cell
(2000)- et al.
Mutations in RCA1 and AFG3 inhibit F1-ATPase assembly in Saccharomyces cerevisiae
FEBS Lett.
(1995) Absence of the mitochondrial AAA protease Yme1p restores F0-ATPase subunit accumulation in an oxa1 deletion mutant of Saccharomyces cerevisiae
J. Biol. Chem.
(2000)
The m-AAA protease defective in hereditary spastic paraplegia controls ribosome assembly in mitochondria
Cell
Extended N-terminal sequencing of proteins of the large ribosomal subunit from yeast mitochondria
FEBS Lett.
A novel two-step mechanism for removal of a mitochondrial signal sequence involves the mAAA complex and the putative rhomboid protease Pcp1
J. Mol. Biol.
Repeat sequence of Epstein-Barr virus-encoded nuclear antigen 1 protein interrupts proteasome substrate processing
J. Biol. Chem.
Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing
Cell
Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria
Cell
Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration
Neuron
A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10)
Am. J. Hum. Genet.
The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses
Cell
Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions
Neuron
Nuclear genes and mitochondrial translation: a new class of genetic disease
Trends Genet.
Mitochondria and neurotransmission: evacuating the synapse
Neuron
Nerve growth factor signaling regulates motility and docking of axonal mitochondria
Curr. Biol.
The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses
Neuron
Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60
Am. J. Hum. Genet.
Distinctive pattern and translational control of mitochondrial protein synthesis in rat brain synaptic endings
J. Biol. Chem.
Molecular and functional analyses of the human and mouse genes encoding AFG3L1, a mitochondrial metalloprotease homologous to the human spastic paraplegia protein
Genomics
Identification and characterization of YME1L1, a novel paraplegin-related gene
Genomics
NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6)
Am. J. Hum. Genet.
Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia
Am. J. Hum. Genet.
The Troyer syndrome (SPG20) protein spartin interacts with Eps15
Biochem. Biophys. Res. Commun.
Molecular motors and mechanisms of directional transport in neurons
Nat. Rev. Neurosci.
Emerging pathways for hereditary axonopathies
J. Mol. Med.
Classification of the hereditary ataxias and paraplegias
Lancet
Advances in the hereditary spastic paraplegias
Exp. Neurol.
Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias
J. Med. Genet.
Cited by (60)
Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia
2021, Journal of the Neurological SciencesCitation Excerpt :There are two isoforms of the m-AAA protease. One is the homo-oligomeric complex formed by only the AFG3L2 protein subunits, and the other is the hetero-oligomeric complex composed by AFG3L2 and paraplegin, a closely related homolog [1]. The m-AAA proteases are responsible for proteostasis regulation and protein quality control in the mitochondria [2], which are essential for multiple mitochondria functions, including oxidative phosphorylation, mitochondria protein synthesis, mitochondrial ribosome assembly, respiratory complex I and III integrity, and mitochondria calcium homeostasis [2–8].
ATPase and Protease Domain Movements in the Bacterial AAA+ Protease FtsH Are Driven by Thermal Fluctuations
2018, Journal of Molecular BiologyThe mitochondrial permeability transition pore in AD 2016: An update
2016, Biochimica et Biophysica Acta - Molecular Cell ResearchMitochondrial ClpP activity is required for cisplatin resistance in human cells.
2016, Biochimica et Biophysica Acta - Molecular Basis of DiseaseHereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms
2014, Experimental NeurologyCitation Excerpt :PGN mutations determine the lack of the paraplegin/AFG3L2 complex, responsible for a specific quality control of proteins that are localized in the inner mitochondrial membrane; moreover, this complex is also involved in a chaperone-like activity on the OXPHOS (oxidative phosphorylation pathway) protein complexes (Maltecca et al., 2009). The impairment in complex I activity has been observed in SPG7 subjects and an increased sensitivity to oxidative stress has been measured in their fibroblasts (reviewed in Rugarli and Langer, 2006). Paraplegin-deficient mice showed axonal degeneration with an abnormal mitochondrial morphology and impairment in axonal transport (Ferreirinha et al., 2004), indicating a role for paraplegin in axon maintenance.