Inherited mitochondrial neuropathies

Finsterer, Josef

doi:10.1016/j.jns.2011.02.012

Cited by 49 publications

(31 citation statements)

References 102 publications

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“…In fact, mitochondrial dysfunction caused by mutations in mitochondrial proteins is the primary trigger of neuronal loss in several examples of neurodegeneration (59). In addition, mutations in the mitochondrial quality control proteins PINK1 and Parkin cause the accumulation of defective mitochondria, leading to PD in humans (60 -62).…”

Section: Discussionmentioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

188

193

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Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

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Section: Discussionmentioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

188

193

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“…Intellectual disability occurs in some individuals. Other variable manifestations include hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis, anemia, sensorineural hearing loss, short stature, autonomic nervous system dysfunction (usually orthostatic hypotension), bladder dysfunction, ventricular hypertrophy, and diverticulosis [103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119].…”

Section: Mngie Diseasementioning

confidence: 99%

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2,

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“…15,16 Interestingly, GDAP1, the most frequent genetic cause for CMT4, encodes a protein anchored to the mitochondrial outer membrane, thus demonstrating that mitochondrial disorders may manifest with demyelinating polyneuropathy as the predominant feature. 1,[15][16][17] The SURF1 gene encodes one of at least 6 assembly factors of COX, the terminal component of the MRC. Studies on yeast and human mutant cells indicate for SURF1 a role in the formation of the early subcomplexes of COX.…”

Section: Characteristics Of the Cmt4 Index Familymentioning

confidence: 99%

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

et al. 2013

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Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-MarieTooth (CMT) disease. Methods:We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A.G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A.G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities ,25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A.G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions:We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. Peripheral neuropathies are a well-known complication of mitochondrial DNA and nuclearencoded mitochondrial gene mutations. For instance, patients with mutations in the nuclearencoded mitochondrial genes MFN2 and GDAP1, which encode outer mitochondrial membrane proteins, usually present with axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease, respectively.1 Moreover, patients with mutations in the mitochondrial DNA gene MTATP6, which encodes the ATP6 subunit of the mitochondrial respiratory chain (MRC) complex V, may present with axonal CMT (CMT2). 2The determination of the genetic cause is a major challenge in rare neuromuscular diseases such as autosomal recessive demyelinating CMT (CMT4). We investigated a consanguineous family in which 2 patients with CMT4 harbored a homozygous splice site mutation in SURF1, encoding an assembly factor of the MRC complex IV (cytochrome c oxidase [COX]). Despite this defect, we detected some residual assembly and function of COX in fibroblasts and muscle of both patients. We then screened for SURF1 mutations in a cohort of 40 unrelated patients

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Inherited mitochondrial neuropathies

Cited by 49 publications

References 102 publications

Loss of Mitochondrial Function Impairs Lysosomes

Loss of Mitochondrial Function Impairs Lysosomes

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

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