ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.
De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.
Åbo Akademi University, Faculty of Natural Sciences and Technology, Turku, Finland.
Helen M
HM
Cooper
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, P.R. China.
Yang
Y
Yang
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Emil
E
Ylikallio
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.|Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia.
Rafil
R
Khairullin
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
Rosa
R
Woldegebriel
Åbo Akademi University, Faculty of Natural Sciences and Technology, Turku, Finland.
Kai-Lan
KL
Lin
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
Liliya
L
Euro
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
Eino
E
Palin
Institute of Molecular Toxicology and Pharmacology, Helmholtz-Zentrum Muenchen-German Research Center for Environmental Health, Neuherberg, Germany.
Alexander
A
Wolf
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
Ras
R
Trokovic
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|Department of Child Neurology, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
Pirjo
P
Isohanni
Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Seppo
S
Kaakkola
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Mari
M
Auranen
Department of Child Neurology, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
Tuula
T
Lönnqvist
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
Sjoerd
S
Wanrooij
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
Henna
H
Tyynismaa
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002547:Cerebral Palsy / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
C549686:ATAD3A protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities