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Overview

Mitochondrial Oxidative Metabolism In Diseases

The main focus of the research in my laboratory is on the regulation of mitochondrial metabolism in diseases associated with mitochondrial dysfunction. We are studying the role of mitochondria in the pathogenesis of neurodegenerative disorders with special emphasis on amyotrophic lateral sclerosis (ALS, Lou Gehrig#146;s disease) and on diseases caused by mutations of the mitochondrial DNA (mtDNA). MtDNA point mutations and rearrangements have been associated with a heterogeneous group of sporadic, mendelian, or maternally-inherited mitochondrial encephalomyopathies. These mutations generally cause an impairment of the respiratory chain, with a reduction in ATP synthesis. However, very little is known about how affected cells cope with impaired energy metabolism. For example, which ATP-dependent cellular functions are preserved and which are down regulated or abolished. It is also unclear which downstream effects mtDNA mutations have on the regulation of mitochondrial biogenesis and on the modulation of mitochondrial functions. We are investigating these complex aspects of mitochondrial biology in health and disease using cybrid cell models, where we are able to transfer various pathogenic mutant mtDNAs from human patients into cells lacking mtDNA but containing a normal nucleus (rho0 cells). We are focusing our studies on post-translational modifications of mitochondrial proteins, such as phosphorylation and oxidation, which are likely to play an important role in modulating the effects of mtDNA mutations. We are also studying the regulation of apoptosis, in mtDNA mutant cells. A growing body of evidence suggests that mitochondrial dysfunction plays a role in the pathogenesis of various neurodegenerative disorders, including ALS. We have demonstrated that familial forms of ALS resulting from mutations in Cu,Zn, superoxide dismutase (SOD1) are characterized by mitochondrial dysfunction. Mutant SOD1 acquires a #147;dominant toxic gain of function#148;, but the mechanisms whereby it causes motor neuron cell death are still unclear. We have shown that SOD1 localizes in mitochondria, where it forms pathogenic aggregates. We are studying the mechanisms underlying the mitochondrial import of mutant SOD1 and its toxic functions. We use both cellular and animal models to investigate mitochondrial dysfunction and its pathogenic mechanisms. Mouse models expressing mutant SOD1 targeted to the mitochondria are being generated to study the specific role of mitochondrial SOD1 in the pathogenesis of familial ALS.

Highlights

  1. 1
    Autophagy · 2021
    HKHibiki Kawamata FujitaGMGiovanni Manfredi
    PMID: 33749521PMCID: PMC8726657DOISenior author43 citations
  2. 2
    Cell reports · 2022
    KMKevin McAvoySCSuzanne CloonanGMGiovanni Manfredi
    PMID: 35263592PMCID: PMC9013208DOISenior author27 citations
  3. 3
    Disease models & mechanisms · 2023
    JAJosef AnratherGMGiovanni Manfredi
    PMID: 37691621PMCID: PMC10581388DOISenior author9 citations

Publications

182 publications

Funding

43 grantsView NIH portfolio on RePORTER ↗

Active

12 grants
  • Co-I
    Role of the Metabolic Homeostasis-ISR axis in C9orf72-ALS/FTD
    National Institute of Neurological Disorders and Stroke · 2026–2031 · via Thomas Jefferson University
    R01NS146192-01A1
  • KP
    Modulating ER stress-induced lipotoxicity to ameliorate mitochondrial myopathy
    Muscular Dystrophy Associations of America, Inc. · 2026–2029
    MDAAA 1454620
  • KP
    CHCHD10 frontotemporal dementia, molecular mechanisms and therapeutic strategies
    National Institute of Neurological Disorders and Stroke · 2024–2029
    R01NS139141-03
  • PI
    Mitochondrial Integrated Stress Response In Neurological Diseases
    National Institute of Neurological Disorders and Stroke · 2021–2029· 2 renewals
    R35NS122209-06
  • MPI
    Modulating ER stress-induced lipotoxicity to ameliorate mitochondrial myopathy
    National Inst of Arthritis & Musculoskeletal & Skin Diseases · 2026–2028
    R21AR087068-01
  • MPI
    Targeting GDF15-GFRAL signaling in mitochondrial myopathies
    National Inst of Arthritis & Musculoskeletal & Skin Diseases · 2025–2027
    R21AR085715-01
  • Co-I
    Role of prohibitin nitrosylation in its neuroprotective functions
    National Institute of Neurological Disorders and Stroke · 2022–2027
    R01NS128034-01
  • PI
    Molecular and cellular mechanisms of cardiac fibrosis in Friedreich ataxia
    Friedreich's Ataxia Research Alliance · 2025–2027
    FARA 245207-02
  • Co-I
    Assessing the combination of Omav, Idebenone, and telmisartan in FA
    Friedreich's Ataxia Research Alliance · 2026–2027
    FARA 260922-01
  • KP
    Genetic and metabolic strategies for mutant CHCHD10 neuromuscular disorders
    Muscular Dystrophy Associations of America, Inc. · 2022–2026
    MDA 961871-03
  • KP
    Metabolic remodeling of skeletal muscle in mitochondrial myopathies
    National Inst of Arthritis & Musculoskeletal & Skin Diseases · 2020–2026
    R01AR076029-05
  • PI
    2025 Mitochondria in Health and Disease Gordon Research Conference and Gordon Research Seminar
    NINDS · 2024–2025 · via NIH RePORTER
    R13NS141243-01
Completed grants (31)
  • PI
    Amylyx SRA
    Amylyx Pharmaceuticals · 2023–2025Contract
    SRA 228283-02
  • Co-I
    Effects of Omav, Idebenone, and Telmisartan in the MCK-FXN KO cardiomyopathy mouse model
    Friedreich's Ataxia Research Alliance · 2024–2025
    FARA 241222-01
  • MPI
    Pathogenic mechanisms and therapeutic strategies for CHCHD10 ALS
    Project ALS, Inc. · 2021–2025
    ALS 215291-02
  • KP
    Iron Homeostasis Alterations In Mutant CHCHD10 Mitochondria
    National Heart, Lung, and Blood Institute · 2021–2024
    F31HL154651-01A1
  • PI
    A novel knock in mouse model to study CHCHD10 mitochondrial diseases
    Muscular Dystrophy Associations of America, Inc. · 2019–2024
    MDA602894-03
  • KP
    Modulation Of Intermediate Metabolism, A New Therapeutic Approach For Mitochondrial Encephalomyopathies
    National Institute of Neurological Disorders and Stroke · 2021–2023
    R21NS118233-01A1
  • PI
    Amylyx: amx0035 (PBA + TUDCA) mechanisms of action
    Amylyx Pharmaceuticals · 2020–2023Contract
    SA 204535-01
  • KP
    Defining the functional role of astrocyte-derived lactate
    National Institute of Neurological Disorders and Stroke · 2020–2023
    F32NS116151-02
  • PI
    The Role Of Calcium Dysregulation In Fa
    Christina Foundation · 2020–2022
    CF 205325-01
  • Sub-PI
    Raloxifene-based therapy in neurodegenerative diseases
    National Institute of Neurological Disorders and Stroke · 2020–2022 · via Icahn School of Medicine at Mount Sinai
    R01NS120477-01
  • PI
    Mitochondrial integrated stress response in FA cardiomyopathy
    Friedreich's Ataxia Research Alliance · 2020–2022
    FRRA 210918-01
  • Co-I
    Role of prohibitin in ischemic brain injury
    National Institute of Neurological Disorders and Stroke · 2020–2022
    R56NS067078-11A1
  • PI
    Biogenic Amines & Amino Acids
    Vanderbilt University · 2019–2022Contract
    SA 194313-01
  • MPI
    Targeting astrocytic toxicity for ALS therapy
    National Institute of Neurological Disorders and Stroke · 2018–2022
    R21NS104520-02
  • PI
    Estrogen Receptor Beta and Mitochondrial Permeability Transition in Ca2+-Induced Neuronal Injury
    National Institute of Neurological Disorders and Stroke · 2016–2022
    R01NS095692-05
  • PI
    The role of the mitochondrial protein dimer CHCHD2/10 in health and disease
    National Institute of Neurological Disorders and Stroke · 2019–2022· 2 renewals
    R01NS112672-02S1
  • PI
    Exploring the disease-modifying effects of EH301 in mouse models of ALS
    Amyotrophic Lateral Sclerosis Association · 2019–2021
    ALS 190452-02
  • PI
    Mitochondria Quality Control In SOD1-ALS
    National Institute of Neurological Disorders and Stroke · 2009–2020· 2 renewals
    R01NS062055-10
  • Sub-PI
    Targeting the mitochondrial UPR in familial ALS
    National Institute of Neurological Disorders and Stroke · 2018–2020 · via Mount Sinai Medical Center
    R21NS109913-02
  • Co-I
    Role of Prohibitin in Ischemic Brain Injury
    National Institute of Neurological Disorders and Stroke · 2009–2020· 2 renewals
    R01NS067078-09
  • PI
    Mitochondrial inter membrane space-IMS unfolded protein response in familial ALS
    NINDS · 2014–2020 · via NIH RePORTER
    R01NS084486-05
  • PI
    Metabolic Profiling of Sporadic ALS Patients: From Fibroblasts to Neurons and Back
    National Institute of Neurological Disorders and Stroke · 2015–2020
    R01NS093872-05
  • Sub-PI
    Mitochondrial Inter Membrane Space - IMS Unfolded Protein in Response in Familial ALS
    National Institute of Neurological Disorders and Stroke · 2014–2019 · via Mount Sinai School of Medicine
    MSSM 5 R01 NS084486-04
  • PI
    CHCHD10 in Familial ALS
    Muscular Dystrophy Associations of America, Inc. · 2016–2019
    MDAAI 16010099-03
  • Co-I
    Metabolic Regulation via Intramitochondrial sAC
    National Institute of General Medical Sciences · 2014–2018
    R01GM107442-04
  • PI
    Modulation of Oxidative Phosphorylation by Mitochondrial Soluble Adenylyl Cyclase in Mitochondrial Diseases
    National Institute of General Medical Sciences · 2011–2016
    R01GM088999-06 EW
  • PI
    Impaired Amino Acid Metabolism in Mitochondrial Diseases
    National Institute of Neurological Disorders and Stroke · 2013–2016
    R21NS084524-02EWO
  • PI
    Mitochondrial Calcium Homeostasis in SOD1-Familial ALS
    National Institute of Neurological Disorders and Stroke · 2010–2016
    R01NS051419-09EWO
  • PI
    Mitochondrial Biogenesis and Dynamics in Health, Disease and Aging
    NIGMS · 2013–2014 · via NIH RePORTER
    R13GM106623-01
  • PI
    Modulation of ATP synthesis in mitochondrial disorders
    NINDS · 2004–2009 · via NIH RePORTER
    K02NS047306-05
  • PI
    ATP SYNTHESIS IN MITOCHONDRIAL DISORDERS
    NINDS · 1999–2004 · via NIH RePORTER
    K23NS002179-05

Available technologies

1 technologyView full WCM portfolio ↗

News mentions

1 mentionView all WCM news ↗
  • Dr. Giovanni Manfredi Awarded NIH Outstanding Investigator Award
    May 14, 2021

    Dr. Giovanni Manfredi, the Finbar and Marianne Kenny Professor in Clinical and Research Neurology at Weill Cornell Medicine’s Feil Family Brain and Mind Research Institute, has received an Outstanding Investigator Award (R35) from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) to study the role of mitochondrial dysfunction in brain disease.

Mentoring

7 menteesAll publications with mentees →

External relationships

Advisory/Scientific Board Member

Fondazione Telethon · Friedreich's Ataxia Research Alliance · Larimar Therapeutics, Inc.