A5023379236- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Cancer, Hypoxia, and Metabolism
- Photosynthetic Processes and Mechanisms
- Metabolism and Genetic Disorders
- Coenzyme Q10 studies and effects
- Cell death mechanisms and regulation
- Organic Chemistry Cycloaddition Reactions
- Redox biology and oxidative stress
- Traditional and Medicinal Uses of Annonaceae
- RNA modifications and cancer
- Chemical Reaction Mechanisms
- Cassava research and cyanide
- Lipid Membrane Structure and Behavior
- Sphingolipid Metabolism and Signaling
- Advanced battery technologies research
- Metabolomics and Mass Spectrometry Studies
- Neonatal Respiratory Health Research
- Insect-Plant Interactions and Control
- Metabolism, Diabetes, and Cancer
- Protein Kinase Regulation and GTPase Signaling
- Drug-Induced Ocular Toxicity
- Cancer-related molecular mechanisms research
- Biological Research and Disease Studies
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
University of Bologna
2015-2025
Istituto delle Scienze Neurologiche di Bologna
2023-2025
Istituti di Ricovero e Cura a Carattere Scientifico
2024
University of Copenhagen
2012
Rigshospitalet
2012
IRCCS Eugenio Medea
2012
University of Pennsylvania
2012
National Institutes of Health
2007
Policlinico S.Orsola-Malpighi
1997
Dominant optic atrophy (DOA) is characterized by retinal ganglion cell degeneration leading to neuropathy. A subset of DOA caused mutations in the OPA1 gene, encoding for a dynamin-related GTPase required mitochondrial fusion. The functional consequences patients are still poorly understood. This study investigated effect five different pathogenic on energetic efficiency and network dynamics skin fibroblasts from patients. Although maintained their ATP levels grew galactose medium, i.e....
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...
Oncocytic tumors are a distinctive class of proliferative lesions composed cells with striking degree mitochondrial hyperplasia that particularly frequent in the thyroid gland. To understand whether specific DNA (mtDNA) mutations associated accumulation mitochondria, we sequenced entire mtDNA 50 oncocytic (45 epithelial cell derivation and 5 mitochondrion-rich breast tumors) 52 control cases (21 nononcocytic tumors, 15 carcinomas, 16 gliomas) by using recently developed technology allows...
Leber's hereditary optic neuropathy, the most frequent mitochondrial disease due to DNA point mutations in complex I, is characterized by selective degeneration of retinal ganglion cells, leading atrophy and loss central vision prevalently young males. The current study investigated reasons for higher prevalence neuropathy males, exploring potential compensatory effects oestrogens on mutant cell metabolism. Control osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 14484/ND6) were grown...
Natural products from the plants of family Annonaceae, collectively called Annonaceous acetogenins, are very potent inhibitors NADH-ubiquinone reductase (Complex I) activity mammalian mitochondria. The properties five such acetogenins compared with those rotenone and piericidin, classical Complex I. Rolliniastatin-1 rolliniastatin-2 more powerful than piericidin in terms both their inhibitory constant protein-dependence titre bovine submitochondrial particles. These could be considered...
Oncocytic tumors are characterized by cells with an aberrant accumulation of mitochondria. To assess mitochondrial function in neoplastic oncocytic cells, we studied the thyroid cell line XTC.UC1 and compared it other non-oncocytic lines. Only were unable to survive galactose, a condition forcing rely solely on mitochondria for energy production. The rate respiration ATP synthesis driven complex I substrates was severely reduced cells. Furthermore, enzymatic activity complexes III...
Leber's hereditary optic neuropathy (LHON), a maternally inherited form of central vision loss, is associated with mitochondrial DNA pathogenic point mutations affecting different subunits complex I. We here report that osteosarcoma-derived cytoplasmic hybrids (cybrid) cell lines harboring one the three most frequent LHON mutations, at positions 11778/ND4, 3460/ND1, and 14484/ND6, undergo death when galactose replaces glucose in medium, contrary to control cybrids maintain some growth...
We have studied the effects of idebenone on mitochondrial function in cybrids derived from one normal donor (HQB17) and patient harboring G3460A/MT-ND1 mutation Leber's Hereditary Optic Neuropathy (RJ206); XTC.UC1 cells bearing a premature stop codon at amino acid 101 MT-ND1 that hampers complex I assembly. Addition to HQB17 caused depolarization NADH depletion, which were inhibited by cyclosporin (Cs) A decylubiquinone, suggesting an involvement permeability transition pore (PTP). On other...
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...
DNAJC15 is a mitochondrial TIMM23-related co-chaperonin known for its role in regulating oxidative phosphorylation efficiency, stress response and lipid metabolism. Recently, it has been proposed that the loss of correlates with cisplatin (CDDP)-resistance onset ovarian cancer (OC), suggesting this protein as potential prognostic factor during OC progression. However, molecular mechanisms through which contributes to CDDP remains poorly investigated. Here, we show high levels are associated...
We report the effect on complex I function of 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting ND6 subunit gene. The same gene was also reported to carry another mutation, at position 14459, associated with LHON/dystonia phenotype that induces a reduction I-specific activity and increases sensitivity product decylubiquinol. Given proximity both mutations in gene, we tested specific its myxothiazol nonylbenzoquinol, inhibitors ubiquinol site, platelet submitochondrial...
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these the G‐to‐A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine histidine 340 subunit ND4 NADH: ubiquinone reductase (respiratory complex I). We report that this amino acid alters affinity I for substrate and induces resistance towards its potent inhibitor rotenone mitochondria LHON patients....
We previously showed that disruptive complex I mutations in mitochondrial DNA are the main genetic hallmark of oncocytic tumors thyroid and kidney. here report a high frequency homoplasmic large panel pituitary head-and-neck tumors. The presence such implicates disassembly respiratory vivo which turn contributes to inability stabilize HIF1α display pseudo-hypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), we induced shift homoplasmy truncating mutation mitochondria-coded...
We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an approximately 50% decrease ATP synthesis) XTC.UC1 (derived from a thyroid oncocytoma bearing disruptive frameshift mutation MT-ND1, which impairs complex I assembly). The addition rotenone antimycin A caused fast membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+...
Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J known increase of 11778/ND4 14484/ND6 mutations. Recently it was also documented that professional exposure n-hexane might act an exogenous trigger for LHON. Therefore, we here investigate...
The oncogenic versus suppressor roles of mitochondrial genes have long been debated. Peculiar features genetics such as hetero/homoplasmy and mutation threshold are seldom taken into account in this debate. Mitochondrial DNA (mtDNA) mutations generally claimed to be protumorigenic, but they also hallmarks mostly benign oncocytic tumors wherein help reduce adaptation hypoxia by destabilizing hypoxia-inducible factor-1α (HIF1α). To determine the influence a disassembling mtDNA its on...
Mitochondrial DNA mutations are currently investigated as modifying factors impinging on tumor growth and aggressiveness, having been found in virtually all cancer types most commonly affecting genes encoding mitochondrial complex I (CI) subunits. However, it is still unclear whether they exert a pro- or anti-tumorigenic effect. We here analyzed the impact of three homoplasmic mtDNA (m.3460G>A/MT-ND1, m.3571insC/MT-ND1 m.3243A>G/MT-TL1) osteosarcoma progression, chosen since induce different...
Abstract Background Aerobic glycolysis, namely the Warburg effect, is main hallmark of cancer cells. Mitochondrial respiratory dysfunction has been proposed to be one major causes for such glycolytic shift. This hypothesis revisited as tumors appear undergo waves gene regulation during progression, some which rely on functional mitochondria. In this framework, role mitochondrial complex I still debated, in particular with respect effect DNA mutations metabolism. The aim work provide proof...
Mitochondria shape is controlled by membrane fusion and fission mediated mitofusins, Opa1, Drp1, whereas mitochondrial motility relies on microtubule motors. These processes govern mitochondria subcellular distribution, whose defects are emphasized in neurons because of their polarized structure. We have studied how perturbation the fusion/fission balance affects distribution Drosophila axons. Knockdown Marf or Opa1 resulted progressive loss distal a distinct oxidative phosphorylation...
Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease characterized by degeneration of retinal ganglion cells (RGCs) and consequent nerve atrophy. Peculiar features LHON are incomplete penetrance gender bias, with marked male prevalence. Based on the different hormonal metabolism between genders, we proposed that estrogens play protective role in females showed these hormones ameliorate mitochondrial dysfunction through estrogen receptors (ERs). We also ERβ...