Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import
Abstract
:1. Introduction
1.1. Mitochondrial Protein Homeostasis
1.2. Mitochondrial Protein Import
2. Skeletal Phenotypes due to Disorders of Mitochondrial Protein Function
2.1. LONP1 and CODAS (Cerebral, Ocular, Dental, Auricular, and Skeletal Syndrome)
2.2. HSPA9 and EVEN-PLUS (Epiphyseal, Vertebral, and Ocular Changes Plus Associated Findings of Severe Microtia, Nasal Hypoplasia, and Other Malformations)
3. Expanding the List of Mitochondrial Skeletal Disorders
3.1. IARS2 and CAGSSS (Cataracts, Growth Hormone Deficiency, Sensory Neuropathy, Sensorineural Hearing Loss, Skeletal Dysplasia Syndrome)
3.2. PAM16 and SMDMDM (Spondylometaphyseal Dysplasia, Megarbane–Dagher–Melki Type)
3.3. AIFM1 and SEMD-HL (Spondyloepimetaphyseal Dysplasia, X-linked, with Hypomyelinating Leukodystrophy)
3.4. PISD
4. Integrating the Mitochondrial Functions Underlying Skeletal Phenotypes
4.1. Linking Mitochondrial Protein Import to Mitochondrial Proteases and Chaperones
4.2. Mitochondrial Lipid Homeostasis
Connecting Mitochondrial Lipids to Mitochondrial Protein Homeostasis and Import
4.3. Mitochondrial tRNAs
4.3.1. Mitochondrial Aminoacyl-tRNA Synthetases
4.3.2. Connecting Mitochondrial tRNAs to Mitochondrial Protein Homeostasis
5. Additional Features in Mitochondrial Skeletal Disorders
6. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Gene | Disorder | Gene Name/Protein Function | Skeletal Phenotypes and Anomalies | Notable Reported Characteristics |
---|---|---|---|---|
LONP1 | CODAS (cerebral, ocular, dental, auricular and skeletal): OMIM 600373 | Lon peptidase 1, mitochondrial. Matrix ATP-dependent protease. | Spondylo-epi-(meta)-physeal dysplasia, short stature, facial dysmorphism, hip dysplasia | Cataracts, developmental delay, dental, hearing loss |
HSPA9 | EVEN-PLUS (epiphyseal, vertebral, ear, nose, plus associated findings): OMIM 616854 | Heat shock protein family A (Hsp70) member 9 (aka Mortalin, mtHsp70, GRP75)/Mitochondrial chaperone. | Spondylo-epi-(meta)-physeal dysplasia, short stature, facial dysmorphism, scoliosis, hip dysplasia | Cataracts, cardiac malformations, dental, genital anomalies, developmental delay |
IARS2 | CAGSSS (cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia): OMIM 616007 | Isoleucyl-tRNA synthetase 2, mitochondrial/tRNA synthetase | Spondylo-epi-(meta)-physeal dysplasia, short stature | Cataracts, neurodevelopmental delay, seizures, peripheral neuropathy hearing loss, growth hormone deficiency |
PAM16 | SMDMDM Spondylometaphyseal dysplasia, Megarbane-Dagher-Melki-type: OMIM 613320 | Presequence translocase associated motor 16. ( aka MAGMAS, TIMM16)/Involved in mitochondrial protein import. | Severe spondylodysplastic dysplasia, short stature, facial dysmorphism | Cardiomyopathy, developmental delay |
AIFM1 | SEMD-HL (Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy): OMIM 300232 | Apoptosis inducing factor mitochondria associated 1/Involved in mitochondrial protein import, apoptosis and assembly of mitochondrial oxidative. phosphorylation complexes. | Spondylo-epi-(meta)-physeal dysplasias, short stature, midface hypoplasia | Myelination, progressive neurodegeneration of the central and peripheral nervous system |
PISD | SEMD (Spondylometaphyseal dysplasia). Liberfarb syndrome: OMIM 618889 | Phosphatidylserine decarboxylase/Converts phosphatidylserine to phosphatidylethanolamine in the IMM. | Spondylo-epi-(meta)-physeal dysplasias, short stature, mid-face hypoplasia | Cataracts, white matter changes |
Gene | Disorder | Gene Name/Protein Function | Reported Skeletal Anomalies | Notable Reported Characteristics |
---|---|---|---|---|
CLPB | MEGCANN (3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia): OMIM 616271 | Caseinolytic mitochondrial matrix peptidase chaperone subunit B/Protein disaggregase associated with IMM (inner mitochondrial membrane. | Extremity rhizomelia, impaired growth, facial dysmorphism | Cataracts, neurologic deterioration, 3-methylglutaconic aciduria, neutropenia |
HSPD1 | SPG13 (Spastic paraplegia 13, autosomal dominant: OMIM 605280. Leukodystrophy, hypomyelinating, 4: OMIM 612233 | Heat shock protein family D (Hsp60) member/Matrix chaperone. | N/A | Dilated cardiomyopathy, leukodystrophy, hypotonia, psychomotor developmental delay, spastic paraplegia |
CLPP | PRLTS3 (Perrault syndrome 3): OMIM 614129 | Caseinolytic mitochondrial matrix peptidase proteolytic subunit/Mitochondrial protease associated with IMM. | Short stature, facial dysmorphism | Premature ovarian failure, ataxia, microcephaly, learning difficulties, sensorineural hearing loss |
SPATA5 | EHLMRS (Epilepsy, Hearing Loss and Mental Retardation Syndrome): OMIM 613940 | Spermatogenesis associated 5. AAA family of ATPases/Unclear molecular function. Role in maintaining mitochondrial function. | Short stature, scoliosis, hip dysplasia | Cataracts, epilepsy, hearing loss and intellectual disability |
HTRA2 | MGCA8 (3-methylglutaconic aciduria type VII): OMIM 617248 | HtrA serine peptidase 2/IMS (inner membrane space) protease associated with IMM. | N/A | Cataracts, 3-methylglutaconic aciduria, seizures, hypotonia, abnormal movements, neutropenia |
AFG3L2 | OPA12 (Optic atrophy 12): OMIM 618977. SPAX5 (Spastic ataxia 5, autosomal recessive): OMIM 614487. SCA28 (Spinocerebellar ataxia 28): OMIM 610246 | AFG3 like matrix AAA peptidase subunit 2/IMM protease. | N/A | Optic atrophy, spinocerebellar ataxia, spastic ataxia, chronic progressive external ophthalmoplegia |
SPG7 | SPG7 (Spastic paraplegia 7, autosomal recessive): OMIM 607259 | SPG7 matrix AAA peptidase subunit, paraplegin/IMM protease. | N/A | Spastic paraplegia, ataxia, optic atrophy, cortical atrophy, cerebellar atrophy, chronic progressive external ophthalmoplegia |
Gene | Disorder | Gene Name/Protein Function | Reported Skeletal Anomalies | Notable Reported Characteristics |
---|---|---|---|---|
TOMM70 | Multi-OXPHOS deficiencies: PMID 31907385 | Translocase of outer mitochondrial membrane 70/Mitochondrial import. | Short stature | Developmental delay, microchephaly, severe anemia, lactic acidosis |
TIMM50 | MGCA9 (3-methylglutaconic aciduria, type IX): OMIM 617698 | Translocase of inner mitochondrial membrane 50/Mitochondrial import. | Short stature, dysmorphic facial features, hip dysplasia, scoliosis and osteoarticular issues | Cardiomyopathy, left ventricle dilation, cardiorespiratory arrest, 3-methylglutaconic aciduria, early-onset seizures, severely delayed psychomotor development, intellectual disability, hypotonia or spasticity |
AGK | Senger syndrome, MTDPS10 (cardiomyopathic mitochondrial DNA depletion syndrome-10): OMIM 212350. CTRCT38 (Cataract 38, autosomal recessive): OMIM 614691 | Acylglycerol kinase/Roles in mitochondrial lipid metabolism and mitochondrial import. | N/A | Cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance |
DNAJC19 | DCMA (Dilated Cardiomyopathy with Ataxia), 3-methylglutaconic aciduria type V (MGCA5): OMIM 610198 | DNAJ heat shock protein family (Hsp40) member C19/Roles in mitochondrial import and cardiolipin metabolism. | Growth retardation | Cataracts, dilated cardiomyopathy, ataxia, 3-methylglutaconic aciduria, genital anomalies |
GFER | MPMCD (Myopathy, mitochondrial progressive, with congenital cataract and developmental delay): OMIM 613076 | Growth factor, augmenter of liver regeneration. (aka ERV1)/Mitochondrial import MIA (mitochondrial import and assembly) component. | Short stature, facial dysmorphology, scoliosis, hip dysplasia | Cataracts, intellectual disability, hearing loss, hypotonia, developmental delay |
PMPCA | SCAR2 (Autosomal Recessive Spinocerebellar Ataxia-2): OMIM 213200 | Peptidase, mitochondrial processing subunit alpha/MTS (mitochondrial targeting sequence) cleavage. | N/A | Cataracts, spinocerebellar ataxia, intellectual disability |
PMPCB | MMDS6 (Multiple mitochondrial dysfunctions syndrome 6): OMIM 617954 | Peptidase, mitochondrial processing subunit beta/MTS cleavage. | N/A | Early onset severe neurodegeneration, hypotonia, intellectual disability, seizures, microcephaly, motor abnormalities |
MIPEP | COXPD31 (Combined oxidative phosphorylation deficiency 31): OMIM 617228 | Mitochondrial intermediate peptidase/MTS cleavage. | Short stature, facial dysmorphology | Cataracts, left ventricular contraction, dilated cardiomyopathy, global developmental delay, severe hypotonia, epilepsy, microcephaly |
XPNPEP3 | NPHPL1 (Nephronophthisis-like nephropathy 1): OMIM 613159 | X-prolyl aminopeptidase 3/MTS cleavage. Role in cilia. | N/A | Hypertrophic dilated cardiomyopathy, renal failure, ciliopathy, essential tremor, hearing loss, muscle fatigue, seizures, and developmental delay |
IMMP2L | Neurodevelopmental disorders: PMID 25478008 | Inner mitochondrial membrane peptidase subunit 2/MTS cleavage. | N/A | Autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia |
Gene | Disorder | Gene Name/Protein Function | Reported Skeletal Anomalies | Notable Reported Characteristics |
---|---|---|---|---|
TAZ | Barth syndrome: OMIM 302060 | Tafazzin/Remodeling of cardiolipin acyl side chains. | Pre-pubertal growth delay, facial dysmorphism | Dilated cardiomyopathy, 3-methylglutaconic aciduria, neutropenia, motor delay |
SERAC1 | MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome):OMIM 614739 | Serine active site containing 1/Mediates phospholipid exchange. | Short stature, scoliosis, dysmorphology | Impaired psychomotor function, encephalopathy, deafness, 3-methylglutaconic aciduria, spasticity |
OPA3 | Costeff Syndrome (3-methylgutaconic aciduria, type III; MGCA3): OMIM 258501. ADOAC (Autosomal Dominant Optic Atrophy and Cataract): OMIM 165300 | Outer mitochondrial membrane lipid metabolism regulator OPA3/Implicated in lipid metabolism | Growth retardation | Cataracts, optic atrophy, early-onset extrapyramidal movement disorder, and cognitive deficits, 3-methylglutaconic aciduria, lipodystrophy |
AGK | Senger syndrome, MTDPS10 (cardiomyopathic mitochondrial DNA depletion syndrome-10): OMIM 212350. CTRCT38 (Cataract 38, autosomal recessive): OMIM 614691 | Acylglycerol kinase/Roles in mitochondrial lipid metabolism and mitochondrial import. | N/A | Cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance |
DNAJC19 | DCMA (Dilated Cardiomyopathy with Ataxia), 3-methylglutaconic aciduria type V (MGCA5): OMIM 610198 | DNAJ heat shock protein family (Hsp40) member C19/Roles in mitochondrial import and cardiolipin metabolism. | Growth retardation | Cataracts, dilated cardiomyopathy, ataxia, 3-methylglutaconic aciduria, genital anomalies |
Gene | Disorder | Gene Name | Reported Skeletal Anomalies | Notable Reported Characteristics |
---|---|---|---|---|
LARS2 | PRLTS4 (Perrault syndrome 4): OMIM 615300 | Leucyl-tRNA synthetase 2, mitochondrial. | Dysmorphic facial features, scoliosis, Marfan habitus | Premature ovarian failure, sensorineural hearing loss |
HARS2 | PRLTS 2 (Perrault syndrome 2): OMIM 614926 | Histidyl-tRNA synthetase 2, mitochondrial. | N/A | Premature ovarian failure, sensorineural hearing loss |
VARS2 | COXPD20 (Combined oxidative phosphorylation deficiency 20): OMIM 615917 | Valyl-tRNA synthetase 2, mitochondrial. | Growth deficiency, facial dymorphisms, hip dysplasia | Hypertrophic cardiomyopathy, muscle weakness, hypotonia, central neurologic disease, epilepsy |
WARS2 | NEMMLAS (Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures): OMIM 617710 | Tryptophanyl tRNA synthetase 2, mitochondrial. | Short stature/growth retardation, dysmorphic features | Delayed psychomotor development, intellectual disability, abnormal motor function, seizures |
GARS | CMT2D (Charcot–Marie–Tooth disease, type 2D): OMIM 601472. HMN5A (Neuronopathy, distal hereditary motor, type VA): OMIM 600794 | glycyl-tRNA synthetase 1. Mitochondrial and cytosolic. | Growth retardation, facial features, scoliosis | Axonal neuropathy, distal motor neuronopathy |
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Zhao, T.; Goedhart, C.; Pfeffer, G.; Greenway, S.C.; Lines, M.; Khan, A.; Innes, A.M.; Shutt, T.E. Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import. Int. J. Mol. Sci. 2020, 21, 8327. https://doi.org/10.3390/ijms21218327
Zhao T, Goedhart C, Pfeffer G, Greenway SC, Lines M, Khan A, Innes AM, Shutt TE. Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import. International Journal of Molecular Sciences. 2020; 21(21):8327. https://doi.org/10.3390/ijms21218327
Chicago/Turabian StyleZhao, Tian, Caitlin Goedhart, Gerald Pfeffer, Steven C Greenway, Matthew Lines, Aneal Khan, A Micheil Innes, and Timothy E Shutt. 2020. "Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import" International Journal of Molecular Sciences 21, no. 21: 8327. https://doi.org/10.3390/ijms21218327