Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by a novel <scp><i>MFF</i></scp> gene mutation in a young child

Panda, Isha; Ahmad, Istaq; Sagar, Shakti; Zahra, Sana; Shamim, Uzma; Sharma, Suvasini; Faruq, Mohammed

doi:10.1111/cge.13740

Cited by 17 publications

(12 citation statements)

References 6 publications

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“…The importance of MFF for human health is highlighted by the fact that several pathogenic variants in MFF have recently been described [24,[244][245][246]. The first report of a pathogenic variant in MFF was a truncating mutation in a patient with delayed psychomotor development, spasticity, Leigh-like encephalopathy and optic atrophy [244].…”

Section: Mitochondrial Fission Factor (Mff)mentioning

confidence: 99%

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

Sharma

Pfeffer

Shutt

2021

Biology

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Mitochondria are dynamic organelles capable of fusing, dividing, and moving about the cell. These properties are especially important in neurons, which in addition to high energy demand, have unique morphological properties with long axons. Notably, mitochondrial dysfunction causes a variety of neurological disorders including peripheral neuropathy, which is linked to impaired mitochondrial dynamics. Nonetheless, exactly why peripheral neurons are especially sensitive to impaired mitochondrial dynamics remains somewhat enigmatic. Although the prevailing view is that longer peripheral nerves are more sensitive to the loss of mitochondrial motility, this explanation is insufficient. Here, we review pathogenic variants in proteins mediating mitochondrial fusion, fission and transport that cause peripheral neuropathy. In addition to highlighting other dynamic processes that are impacted in peripheral neuropathies, we focus on impaired mitochondrial quality control as a potential unifying theme for why mitochondrial dysfunction and impairments in mitochondrial dynamics in particular cause peripheral neuropathy.

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Section: Mitochondrial Fission Factor (Mff)mentioning

confidence: 99%

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

Sharma

Pfeffer

Shutt

2021

Biology

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“…Several patients with MFF deficiency, a rare autosomal recessive neurological disorder (OMIM#617086), have been identified. This is caused by various mutations in the MFF gene, all of which (except one) lead to a truncated protein lacking the C-terminal TMD and tail ( Appendix A ) [c.C190T:p.Q64* [ 119 ]; c.184dup:p.L62Pfs*13 combined with c.C892T:p.R298* [ 120 ]; c.453_454del:p.E153Afs*5 [ 120 ]); c.C892T:p.R298* [ 121 ]; c.C433T:p.R145* [ 122 ]; c.19_20delAGinsTT:p.S7F [ 123 ]]. MFF truncations with a loss of the C-terminal TMD and tail will abolish the targeting and membrane localization of MFF, resulting in its absence at mitochondria and peroxisomes.…”

Section: Disorders Of Peroxisome Dynamics and Plasticitymentioning

confidence: 99%

“…MFF truncations with a loss of the C-terminal TMD and tail will abolish the targeting and membrane localization of MFF, resulting in its absence at mitochondria and peroxisomes. Those patients show neurological abnormalities with onset during the first year of life and may present with Leigh-like encephalopathy, developmental delay, peripheral neuropathy, optic atrophy, and microcephaly [ 119 , 120 , 121 , 122 ]. A recent case with an amino acid change from serine to phenylalanine at position 7 was reported [ 123 ].…”

Section: Disorders Of Peroxisome Dynamics and Plasticitymentioning

confidence: 99%

“…Like many inherited disorders, there are currently no clinically approved cures for patients with a defect in mitochondria and/or peroxisomal fission, and treatments are generally focused on alleviating symptoms, for example anticonvulsants to counter seizures [ 179 ]. Several MFF-deficient patients [ 121 , 122 ] and a PEX11β-deficient patient [ 130 ] have been reported to respond positively to treatment with a mitochondrial drug cocktail, which either offers mild improvement or at least halts deterioration. Such cocktails typically consist of antioxidants, such as riboflavin, thiamine, carnitine and Co-enzyme Q10, which also bolster mitochondrial function in patients where this might be compromised, e.g., by promoting electron transport chain function (Co-enzyme Q10, riboflavin) or mitochondrial β-oxidation (carnitine) [ 180 ].…”

Section: Potential Strategies For Treatmentmentioning

confidence: 99%

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Fission Impossible (?)—New Insights into Disorders of Peroxisome Dynamics

Carmichael

Islinger

Schrader

2022

Cells

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Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas the metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with a particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome–ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome–ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussed.

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“…Neuroimaging revealed basal ganglia signal abnormalities. Cultured fibroblasts from patients displayed tubular, elongated, and hyperfused mitochondria and peroxisomes, indicating organelle fission defects [130][131][132][133].…”

Section: Mffmentioning

confidence: 99%

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

Nottia

Verrigni

Torraco

et al. 2021

Genes

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Mitochondria do not exist as individual entities in the cell—conversely, they constitute an interconnected community governed by the constant and opposite process of fission and fusion. The mitochondrial fission leads to the formation of smaller mitochondria, promoting the biogenesis of new organelles. On the other hand, following the fusion process, mitochondria appear as longer and interconnected tubules, which enhance the communication with other organelles. Both fission and fusion are carried out by a small number of highly conserved guanosine triphosphatase proteins and their interactors. Disruption of this equilibrium has been associated with several pathological conditions, ranging from cancer to neurodegeneration, and mutations in genes involved in mitochondrial fission and fusion have been reported to be the cause of a subset of neurogenetic disorders.

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Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by a novel MFF gene mutation in a young child

Cited by 17 publications

References 6 publications

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

Fission Impossible (?)—New Insights into Disorders of Peroxisome Dynamics

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

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