A5039977222- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- Adipose Tissue and Metabolism
- Pluripotent Stem Cells Research
- Nerve injury and regeneration
- RNA modifications and cancer
- 3D Printing in Biomedical Research
- Genetic Neurodegenerative Diseases
- Neuroscience and Neural Engineering
- Neurogenesis and neuroplasticity mechanisms
- Diet and metabolism studies
- Cancer, Hypoxia, and Metabolism
- Liver Disease Diagnosis and Treatment
- Stroke Rehabilitation and Recovery
- Tissue Engineering and Regenerative Medicine
- Myasthenia Gravis and Thymoma
- Connective tissue disorders research
- Single-cell and spatial transcriptomics
- Immune cells in cancer
- Bone Tissue Engineering Materials
- Neuroscience and Neuropharmacology Research
- Histone Deacetylase Inhibitors Research
- Protein Tyrosine Phosphatases
- Peripheral Neuropathies and Disorders
University of Verona
2020-2025
University of Brescia
2019-2024
National Hospital for Neurology and Neurosurgery
2020
Medical Research Council
2016-2020
University College London
2020
MRC Mitochondrial Biology Unit
2015-2020
Great Ormond Street Hospital
2020
University of Cambridge
2017-2018
Wellcome Trust
2017-2018
University of Helsinki
2016
Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1α-dependent homeostatic pathways has been proposed as a treatment for disease. We tested this hypothesis on three recombinant mouse models characterized defective cytochrome c-oxidase (COX) activity: knockout (KO) Surf1, knockout/knockin Sco2, and muscle-restricted KO Cox15. First, we demonstrated that double-recombinant animals overexpressing PGC-1α in skeletal muscle Surf1 background showed robust induction increase...
To validate new mitochondrial myopathy serum biomarkers for diagnostic use.We analyzed FGF21 (S-FGF21) and GDF15 from patients with (1) diseases (2) nonmitochondrial disorders partially overlapping disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in disease (4) S-Fgf21 skeletal muscle Fgf21 expression 6 mouse models different muscle-manifesting dysfunctions.We report that consistently increases primary myopathy, especially translation defects or DNA (mtDNA) deletions (675 347...
Abstract Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and currently incurable. The lack effective models hampers our understanding the mechanisms underlying neuronal pathology LS. Using patient-derived induced pluripotent stem cells CRISPR/Cas9 engineering, we developed human model LS caused by mutations complex IV assembly gene SURF1 . Single-cell RNA-sequencing multi-omics analysis revealed compromised morphogenesis mutant neural cultures brain...
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors owing to its robust desmoplasia, low immunogenicity, and recruitment cancer-conditioned, immunoregulatory myeloid cells. These features strongly limit success immunotherapy as a single agent, thereby suggesting need for development multitargeted approach. The goal foster T lymphocyte infiltration within tumor landscape neutralize cancer-triggered immune suppression, enhance therapeutic effectiveness...
Mutations in human MPV17 cause a hepatocerebral form of mitochondrial DNA depletion syndrome (MDS) hallmarked by early-onset liver failure, leading to premature death. Liver transplantation and frequent feeding using slow-release carbohydrates are the only available therapies, although surviving patients eventually develop slowly progressive peripheral central neuropathy. The physiological role Mpv17, including its functional link (mtDNA) maintenance, is still unclear. We show here that...
The age-dependent decline of skeletal muscle and cognitive function often coexist in elderly subjects share common pathophysiological mechanisms, including mitochondrial dysfunctions, which can prelude to overt sarcopenia and/or dementia. Dietary supplementation with formulations essential branched-chain amino acids (EAA-BCAA) is a promising preventive strategy because it preserve biogenesis function. senescence-accelerated mouse-prone 8 (SAMP8) considered an accurate model age-related...
Dysregulations of mitochondria with alterations in trafficking and morphology these organelles have been related to Parkinson’s disease (PD), a neurodegenerative disorder characterized by brain accumulation Lewy bodies (LB), intraneuronal inclusions mainly composed α -synuclein ( -syn) fibrils. Experimental evidence supports that -syn pathological aggregation can negatively impinge on mitochondrial functions suggesting this protein may be crucially involved the control homeostasis. The aim...
A growing interest in the study of aerobic glycolysis as a key pathway for cancer-cell energetic metabolism, favouring tumour progression and invasion, has led to consider GAPDH an effective drug target specifically hit cancer cells. In this study, we have investigated panel 3-bromo-isoxazoline derivatives based on previously identified inhibitors Plasmodium falciparum (PfGAPDH). The compounds are active, different extent, human-recombinant GAPDH. They showed antiproliferative effect...
Here we present a protocol to generate standardized cerebral organoids with hippocampal regional specification using morphogen WNT3a. We describe steps for isolating mouse embryonic (E14.5) neural stem cells from the brain subgranular zone, preparing samples immunofluorescence, calcium imaging, and metabolic profiling. This can be used developmental studies, modeling disease, drug screening. Organoids obtained in one month, thus providing rapid tool high-throughput data validation. For...
To describe the clinical and functional consequences of 1 novel previously reported truncating MT-ATP6 mutation.Three unrelated probands with mitochondrial encephalomyopathy harboring mutations are reported. Transmitochondrial cybrid cell studies were used to confirm pathogenicity variant, effects all 3 on ATPase 6 complex V structure function investigated.Patient presented adult-onset cerebellar ataxia, chronic kidney disease, diabetes, whereas patient 2 had myoclonic epilepsy ataxia; both...
Brain organoids are in vitro three-dimensional (3D) self-organized neural structures, which can enable disease modeling and drug screening. However, their use for standardized large-scale screening studies is limited by high batch-to-batch variability, long differentiation time (10-20 weeks), production costs. This particularly relevant when brain obtained from human induced pluripotent stem cells (iPSCs). Here, we developed, the first time, a highly standardized, reproducible, fast (5...
Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of is Leigh syndrome (LS) causing psychomotor regression metabolic crises. To accelerate drug discovery for LS, we screened a library 5,632 repurposable compounds in induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) from LS patients. We identified phosphodiesterase 5 inhibitors (PDE5i) as leads, prioritized sildenafil due to its safety profile....
Leigh syndrome (LS) associated with cytochrome c oxidase (COX) deficiency is an early onset, fatal mitochondrial encephalopathy, leading to multiple neurological failure and eventually death, usually in the first decade of life. Mutations SURF1, a nuclear gene encoding protein involved COX assembly, are among most common causes LS. LSSURF1 patients display severe, isolated all tissues, including cultured fibroblasts skeletal muscle. Recombinant, constitutive SURF1−/− mice show diffuse...
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with an overall 5-year survival rate less than 9%. The high aggressiveness PDAC linked to presence a subpopulation cells greater tumorigenic capacity, generically called stem (CSCs). CSCs present heterogeneous metabolic profile that might be supported by adaptation mitochondrial function; however, role this organelle in development and maintenance remains controversial. To determine mitochondria over longer...
Non-alcoholic fatty liver disease (NAFLD) is a health emergency worldwide due to its high prevalence and the lack of specific therapies. Noninvasive biomarkers supporting NAFLD diagnosis are urgently needed. Liver mitochondrial dysfunction central pathomechanism that changes throughout progression. Blood-cell bioenergetics reflecting organ emerging for potential applications in diagnostics. We measured real-time respirometry peripheral blood mononuclear cells (PBMCs), anthropometric...
Introduction: Biallelic variants in PITRM1 are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is mitochondrial matrix enzyme, which digests diverse oligopeptides, including the targeting sequences (MTS) that cleaved from proteins imported across inner membrane processing peptidase (MPP). Mitochondrial peptidases also play role maturation of Frataxin,...