Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28

Bella, Daniela Di; Lazzaro, Federico; Brusco, Alfredo; Plumari, Massimo; Battaglia, Giorgio; Pastore, Annalisa; Finardi, Adele; Cagnoli, Claudia; Tempia, Filippo; Frontali, Marina; Veneziano, Liana; Sacco, Tiziana; Boda, Enrica; Brussino, Alessandro; Bonn, Florian; Castellotti, Barbara; Baratta, Silvia; Mariotti, Caterina; Gellera, Cinzia; Fracasso, Valentina; Magri, Stefania; Langer, Thomas; Plevani, Paolo; Donato, Stefano Di; Muzi-Falconi, Marco; Taroni, Franco

doi:10.1038/ng.544

Cited by 290 publications

(305 citation statements)

References 49 publications

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“…Interestingly, mutations that affect only hetero-oligomeric or both hetero-and homo-oligomeric human m-AAA protease complexes are linked to two distinct neurological disorders. Although mutations in the Paraplegin subunit are responsible for hereditary spastic paraplegia (12), it was shown more recently that mutations in AFG3L2 cause a dominant form of hereditary spinocerebellar ataxia (SCA28) (13). These findings raise the question whether homo-and hetero-oligomeric complexes are functionally and mechanistically equivalent.…”

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confidence: 77%

“…It is therefore conceivable that alterations of amino acid residues at the PD interface during evolution gave rise to homo-and hetero-oligomeric m-AAA protease complexes and fine-tuned their specific cellular activities. Interestingly, mutations in Yta12, which allow homooligomerization, cluster within the same region of the PD as disease-causing mutations in SCA28 patients (13), suggesting that these mutations may also affect assembly of human m-AAA proteases.…”

Section: Determinants For Hetero-oligomeric Assembly Of M-aaamentioning

confidence: 99%

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Electron Cryomicroscopy Structure of a Membrane-anchored Mitochondrial AAA Protease

Lee

Augustin

Tatsuta

et al. 2011

Journal of Biological Chemistry

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FtsH-related AAA proteases are conserved membrane-anchored, ATP-dependent molecular machines, which mediate the processing and turnover of soluble and membrane-embedded proteins in eubacteria, mitochondria, and chloroplasts. Homo-and hetero-oligomeric proteolytic complexes exist, which are composed of homologous subunits harboring an ATPase domain of the AAA family and an H41 metallopeptidase domain. Mutations in subunits of mitochondrial m-AAA proteases have been associated with different neurodegenerative disorders in human, raising questions on the functional differences between homo-and hetero-oligomeric AAA proteases. Here, we have analyzed the hetero-oligomeric yeast m-AAA protease composed of homologous Yta10 and Yta12 subunits. We combined genetic and structural approaches to define the molecular determinants for oligomer assembly and to assess functional similarities between Yta10 and Yta12. We demonstrate that replacement of only two amino acid residues within the metallopeptidase domain of Yta12 allows its assembly into homo-oligomeric complexes. To provide a molecular explanation, we determined the 12 Å resolution structure of the intact yeast m-AAA protease with its transmembrane domains by electron cryomicroscopy (cryo-EM) and atomic structure fitting. The full-length m-AAA protease has a bipartite structure and is a hexamer in solution. We found that residues in Yta12, which facilitate homo-oligomerization when mutated, are located at the interface between neighboring protomers in the hexamer ring. Notably, the transmembrane and intermembrane space domains are separated from the main body, creating a passage on the matrix side, which is wide enough to accommodate unfolded but not folded polypeptides.These results suggest a mechanism regarding how proteins are recognized and degraded by m-AAA proteases.Energy-dependent proteases form oligomeric ring complexes and harbor conserved ATPase domains of the AAA ϩ family (1). It is widely accepted that AAA ϩ machines utilize the energy derived from ATP hydrolysis to thread substrate proteins through a central pore resulting in substrate unfolding. FtsH-related AAA proteases form a distinct membraneassociated group of AAA ϩ machines, present in eubacteria and in mitochondria and chloroplasts of eukaryotic cells (2, 3). Members of this group feature an N-terminal membrane targeting signal, followed by one or two transmembrane helices, and a canonical AAA domain that is covalently linked to the metallopeptidase domain (3, 4).X-ray crystal structures of the soluble cytosolic domains of the bacterial AAA protease FtsH (FtsH Cyt ) bound to ADP and in the absence of nucleotide (apo) have been reported (5-7). Although the AAA ring of the apo-FtsH Cyt hexamer was 6-fold symmetric (7), the ADP-bound structures revealed a 2-(6) and 3-fold symmetrical hexamer (5). However, the protease ring was 6-fold symmetric in all three structures. Therefore, it remained unclear what symmetry the full-length protease adopts and which of the stereo-specific interactions between ne...

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confidence: 77%

Section: Determinants For Hetero-oligomeric Assembly Of M-aaamentioning

confidence: 99%

Electron Cryomicroscopy Structure of a Membrane-anchored Mitochondrial AAA Protease

Lee

Augustin

Tatsuta

et al. 2011

Journal of Biological Chemistry

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“…Mgr1 and Mgr3 have been proposed to act as substrate adaptors of the yeast i-AAA protease, required for the turnover of misfolded substrates (Dunn et al 2008). The importance of quality control across the IM is highlighted by the finding that mutations in both of the genes encoding for paraplegin and Afg3l2 lead to the neurological diseases hereditary spastic paraplegia (HSP) and spinocerebellar ataxia type 28 (SCA28), respectively (Rugarli and Langer 2006;Martinelli et al 2009;Di Bella et al 2010;Martinelli and Rugarli 2010).…”

Section: Protein Quality Control Across the Mitochondrial Immentioning

confidence: 99%

Quality Control of Mitochondrial Proteostasis

Baker

Tatsuta²,

Langer

2011

Cold Spring Harbor Perspectives in Biology

223

193

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A decline in mitochondrial activity has been associated with aging and is a hallmark of many neurological diseases. Surveillance mechanisms acting at the molecular, organellar, and cellular level monitor mitochondrial integrity and ensure the maintenance of mitochondrial proteostasis. Here we will review the central role of mitochondrial chaperones and proteases, the cytosolic ubiquitin-proteasome system, and the mitochondrial unfolded response in this interconnected quality control network, highlighting the dual function of some proteases in protein quality control within the organelle and for the regulation of mitochondrial fusion and mitophagy.

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“…7 Mutations in the mitochondrial m-AAA proteases are responsible for neurodegenerative disorders including hereditary spastic paraplegia (HSP), spinocerebellar ataxia (SCA28) and spastic ataxia neuropathy syndrome. [8][9][10] However, the degenerative mechanisms remain elusive, 11 and the presence of multiple mitochondrial m-AAA proteases with redundant functions in eukaryotes complicates their analysis in animal models. By contrast, only one mitochondrial i-AAA protease has been identified in eukaryotic genomes.…”

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confidence: 99%

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

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Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28

Cited by 290 publications

References 49 publications

Electron Cryomicroscopy Structure of a Membrane-anchored Mitochondrial AAA Protease

Electron Cryomicroscopy Structure of a Membrane-anchored Mitochondrial AAA Protease

Quality Control of Mitochondrial Proteostasis

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

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