A5040116544- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Metabolism and Genetic Disorders
- Endoplasmic Reticulum Stress and Disease
- Photosynthetic Processes and Mechanisms
- RNA modifications and cancer
- Autophagy in Disease and Therapy
- Cancer, Hypoxia, and Metabolism
- Cytokine Signaling Pathways and Interactions
- Pediatric Hepatobiliary Diseases and Treatments
- Chemical Reactions and Isotopes
- Metabolomics and Mass Spectrometry Studies
- Cell death mechanisms and regulation
- Fibroblast Growth Factor Research
- Folate and B Vitamins Research
- Medical Imaging Techniques and Applications
- Alzheimer's disease research and treatments
- Infectious Encephalopathies and Encephalitis
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Metalloenzymes and iron-sulfur proteins
- Lysosomal Storage Disorders Research
- Ubiquitin and proteasome pathways
- GDF15 and Related Biomarkers
- Genomics and Rare Diseases
- Ion Transport and Channel Regulation
University of Bologna
2015-2024
Istituto delle Scienze Neurologiche di Bologna
2022-2024
California Institute of Technology
2017
OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long short forms, but it unclear whether functions associated with specific and/or domains. To address this, we each the or different constructs isoform 1 in Opa1−/− MEFs. We observed any could restore structure, abundance, energetic efficiency independently network morphology. Long forms supported fusion; were better able to efficiency....
Objective Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer with mitochondrial dysfunction, recent emphasis has focused on dynamics quality control. Mitochondrial mtDNA maintenance is another link recently emerged, implicating mutations in the fusion genes OPA1 MFN2 pathogenesis of multisystem syndromes characterized by neurodegeneration accumulation multiple deletions postmitotic tissues. Here, we report 2 Italian families affected dominant chronic...
Abstract Leber’s hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased biogenesis in unaffected mutation carriers a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking...
Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the single-strand binding protein (SSBP1) in 4 families dominant 1 recessive inheritance. show that SSBP1 patient-derived...
Leber's hereditary optic neuropathy (LHON), a disease associated with mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the nerve.We show that sustained pathological autophagy compartment-specific mitophagy activity affects LHON patient-derived cybrids, as well induced pluripotent-stem-cell-derived neurons.This variably counterbalanced compensatory mitobiogenesis.The aberrant quality control disrupts...
Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% patients, but we can neither predict nor understand non-responders. Idebenone is reduced by cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons respiratory complex III, bypassing affected LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers...
Mitochondrial ATP synthase (Complex V) catalyzes the last step of oxidative phosphorylation and provides most energy (ATP) required by human cells. The mitochondrial genes MT-ATP6 MT-ATP8 encode two subunits multi-subunit Complex V. Since discovery first variant in year 1990 as cause Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) syndrome, a large continuously increasing number inborn variants have been identified pathogenic. Variants these correlate with various clinical phenotypes, which...
Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or nuclear genome. In this study, we investigated a panel of blood biomarkers cohort 123 patients, with prominent neurological and muscular manifestations. These included creatine, fibroblast growth factor 21 (FGF21) growth/differentiation 15 (GDF-15), novel cell free circulating-mtDNA (ccf-mtDNA). All were significantly increased patient group. After...
We here report on the existence of Leber’s hereditary optic neuropathy (LHON) associated with peculiar combinations individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting MT-ND4, MT-ND4L and MT-ND6 subunit genes Complex I. The pathogenic potential these mtDNA haplotypes is supported by multiple evidences: first, LHON phenotype strictly inherited along maternal line in one very large family; second, variants are unique to two lineages that characterized recurrence...
Abstract Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent mitochondrial diseases. The role played mitochondria remains elusive, with contradictory results on occurrence dysfunction. We evaluated 13 WS patients deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest after standardized exercise, brain Magnetic Resonance Imaging, muscle Spectroscopy (MRS). Finally,...
Objective Dominant optic atrophy (DOA) is the most common inherited neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% DOA patients, significant number remaining undiagnosed. Methods We screened 286 index cases presenting atrophy, negative for mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms identified variants were studied yeast patient‐derived fibroblasts. Results Twelve (4%) carry novel...
Abstract Interpretation of variants uncertain significance is an actual major challenge. We addressed this question on a set OPA1 missense responsible for variable severity neurological impairments. used targeted metabolomics to explore the different signatures expressed in Opa1 deleted mouse embryonic fibroblasts (Opa1−/− MEFs), grown under selective conditions. Multivariate analyses data discriminated Opa1+/+ from Opa1−/− MEFs metabolic and classified according their vitro severity....
ADCA-DN and HSN-IE are rare neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence (RFTS) of DNA methyltransferase 1 (DNMT1) gene. Both phenotypes resemble mitochondrial disorders, dysfunction was first observed ADCA-DN. To explore involvement, we studied effects DNMT1 fibroblasts from four two patients. We documented impaired activity purified mutant proteins, which results increased amount. demonstrated that is not localized within mitochondria,...
The endogenous inhibitor of mitochondrial F1Fo-ATPase (ATP synthase), IF1, has been shown to exert pro-oncogenic actions, including reprogramming cellular energy metabolism (Warburg effect). latter action IF1 reported be hampered by its PKA-dependent phosphorylation, but both and phosphorylation are intensely debated. To clarify these critical issues, we prepared stably IF1-silenced clones compared their bioenergetics with that the three parental IF1-expressing cancer cell lines. All...
Changes of quantity and/or morphology cell mitochondria are often associated with metabolic modulation, pathology, and apoptosis. Exogenous fluorescent probes used to investigate changes in mitochondrial content dynamics strongly dependent, for their internalization, on the membrane potential composition, thus limiting reliability measurements. To overcome this limitation, genetically encoded recombinant proteins, targeted different cellular districts, were as reporters. Here, we explored...
Abstract OPA1 mutations are the major cause of dominant optic atrophy (DOA) and syndromic form DOA plus, pathologies for which there is no established cure. We used a ‘drug repurposing’ approach to identify FDA-approved molecules able rescue mitochondrial dysfunctions induced by mutations. screened two different chemical libraries using yeast strains carrying mgm1I322M chim3P646L mutations, identifying 26 drugs their oxidative growth phenotype. Six them, reduce DNA instability in yeast, have...
Cancer cells overexpress IF1, the endogenous protein that inhibits hydrolytic activity of ATP synthase when mitochondrial membrane potential (ΔμH+) falls, as in ischemia. Other roles have been ascribed to but associated molecular mechanisms are still under debate. We investigated ability IF1 promote survival and proliferation osteosarcoma colon carcinoma exposed conditions mimicking ischemia reperfusion, occurs vivo, particularly solid tumors. IF1-silenced parental were FCCP uncoupler...
Abstract Background Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in DNA (mtDNA) most frequently affecting the tRNA Lys gene at position m.8344A > G. Defective severely impairs protein synthesis respiratory chain when high percentage of mutant heteroplasmy crosses threshold for full-blown clinical phenotype. Therapy currently limited symptomatic management myoclonic epilepsy, supportive measures counteract muscle...
An amendment to this paper has been published and can be accessed via a link at the top of paper.
Idebenone is the only approved treatment for Leber's hereditary optic neuropathy (LHON). It promotes recovery of visual function in up to 50% patients, but, based on current knowledge, we can neither predict nor understand non‐responders. reduced by cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons respiratory complex III, bypassing affected LHON. We explored possibility that genetic variant NQO1 enzyme impact idebenone response. found two polymorphic variants...