ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia

Abstract

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.

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

“…In patient cell lines, supercomplexes consisting of OXPHOS complexes I, III and IV in various stoichiometries are destabilized, resulting in impaired OXPHOS efficiency (48,50). On the other hand, the ATAD3 locus, recently identified to underlie diverse clinical presentations often involving cerebellar defects (51)(52)(53), is linked to mitochondrial functions that include regulation of mtDNA maintenance and translation. ATAD3 patient cell lines show defects in cellular cholesterol and mtDNA homeostasis, providing a basis for the disease pathology, yet a clear link between ATAD3 and OXPHOS impairment is still lacking (52).…”

ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels

“…In the past few years, mutations in ATAD3 genes have been associated with different neurological syndromes. Dominant point mutations (Cooper et al, 2017;Harel et al, 2016), a recessive point mutation (Harel et al, 2016) and biallelic deletions (Desai et al, 2017;Harel et al, 2016) have been described.…”

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism

“…Since its initial association with a neurological disorder, 1 it has become apparent that disruption of the ATAD3 cluster, and more specifically ATAD3A (MIM: 612316), is a significant cause of pediatric disease. Variants at this locus are associated with a wide phenotypic spectrum, including pontocerebellar hypoplasia, 2 hereditary spastic paraplegia, 3 and a syndromic neurological disorder characterized by peripheral neuropathy, hypotonia, cardiomyopathy, optic atrophy, cerebellar atrophy, and seizures: 1 Harel-Yoon syndrome (HAYOS [MIM: 617183]). The different phenotypes can be attributed to a spectrum of disease-causing variants that includes bi-allelic hypomorphic variants, bi-allelic deletions, and monoallelic dominant-negative missense variants.…”

“…2,7,8 More recently it has been shown to interact with Drp1/DNM1L to support Drp1-induced mitochondrial division, 9 a process that drives mtDNA segregation. 10,11 Concordantly, ATAD3 dysfunction and deficiency have a wide range of effects on mitochondrial structure and function, characterized by disturbed mitochondrial morphology and fission dynamics, 3,6 loss of cristae, 12 perturbed mtDNA and cholesterol metabolism, impaired mitochondrial steroidogenesis, 2,13 and decreased levels of some mitochondrial oxidative phosphorylation (OXPHOS) components. 12 It is not clear whether the disruption to the inner mitochondrial membrane, mtDNA, and OXPHOS complexes are due directly to the absence of ATAD3 4,12 or whether they are consequences of changes to membrane architecture resulting from an altered cholesterol content 2,13 or a combination of the two.…”