Yeast NDI1 rescues muscular NDUFS3-/- mouse model: a new prospect of flexible gene therapy for complex-I deficiencies.

Elenco Abstract

Daniele Sala

Yeast NDI1 rescues muscular NDUFS3-/- mouse model: a new prospect of flexible gene therapy for complex-I deficiencies.

Autori

DANIELE SALA (FOUNDATION IRCCS NEUROLOGICAL INSTITUTE CARLO BESTA, MILAN (ITALY) – MEDICAL BIOTECHNOLOGIST)
SILVIA MARCHET (FOUNDATION IRCCS NEUROLOGICAL INSTITUTE CARLO BESTA, MILAN (ITALY) – BIOLOGIST)
COSTANZA LAMPERTI (FOUNDATION IRCCS NEUROLOGICAL INSTITUTE CARLO BESTA, MILAN (ITALY) – MEDICAL DOCTOR)
HOLGER PROKISCH (COMPUTATIONAL HEALTH CENTER, HELMHOLTZ CENTER MUNICH, NEUHERBERG, GERMANY; INSTITUTE OF HUMAN GENETICS, SCHOOL OF MEDICINE, TECHNICAL UNIVERSITY OF MUNICH, MUNICH, GERMANY) – BIOLOGIST
NATHALIA DRAGANO (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)
BIRGIT RATHKOLB (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)
ANTONIO AGUILAR-PIMENTEL (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)
OANA AMARIE (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY) – BIOLOGIST (ANIMAL MODELS)
LORE BECKER (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY) – BIOLOGIST (ANIMAL MODELS)
JULIA CALZADA-WACK (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)
PATRICIA DA SILVA-BUTTKUS (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY) – BIOLOGIST (ANIMAL MODELS)
LILLIAN GARRETT (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY) – BIOLOGIST (ANIMAL MODELS)
SABINE HÖLTER (INSTITUTE OF DEVELOPMENTAL GENETICS, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH, NEUHERBERG, GERMANY) – BIOLOGIST (ANIMAL MODELS)
ADRIÁN SANZ-MORENO (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)
NADINE SPIELMANN (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)
HELMUT FUCHS (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)
VALERIE GAILUS-DURNER
Affiliazione: INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY
Specializzazione: BIOLOGIST (ANIMAL MODELS)
MARTIN HRABĚ DE ANGELIS (INSTITUTE OF EXPERIMENTAL GENETICS, GERMAN MOUSE CLINIC, HELMHOLTZ ZENTRUM MÜNCHEN, GERMAN RESEARCH CENTER FOR ENVIRONMENTAL HEALTH (GMBH), NEUHERBERG, GERMANY – BIOLOGIST (ANIMAL MODELS)

Presentatore

DANIELE SALA FOUNDATION IRCCS NEUROLOGICAL INSTITUTE CARLO BESTA, MILAN (ITALY)

Modalità

Oral Communication

Abstract

Mitochondrial myopathies encompass a broad variety of genetic conditions and phenotypic manifestations, very often framed within complex multi-systemic diseases. Many of them originate from defective mitochondrial complex-I and other damaged OXPHOS components. Therapeutic options for such disorders are still scarcely available and offer quite limited efficacy. Gene therapy attempts are currently under development, aimed to precision medicine interventions able to correct specific genes or specific mutations. In this study, we investigated in vivo the potential “one-size fits all” strategy to revert complex-I deficiencies, using the alternative OXPHOS enzyme NDI1 from Saccharomyces cerevisiae. Murine models were genetically engineered with muscle-specific Knock-In (KI) of NDI1 gene and subsequently crossed with myopathic mouse line harbouring muscle-conditional Knock-Out (KO) of NDUFS3 gene (complex-I subunit). KI mice showed mild increase of systemic metabolism, heat production and reduced body mass. However, no pathological features were detected. After inbreeding with KO mice, the phenotypic rescue was evaluated at multiple levels: histological and biochemical analyses revealed an evident morphological improvement and the functional recovery of complex-I activity inside mitochondria, while phenotypic evaluations reported complete or partial reversal of several features, including muscle performance at rotarod, body weight parameters, energy metabolism and circulating biomarkers such as lactate and FGF21. Overall, the mortality of myopathic mice was 50% decreased by introducing NDI1 gene.
In this work, we demonstrated the rescuing effects of yeast NDI1 in mice lacking NDUFS3 gene in skeletal muscles, describing a promising and flexible strategy that could be applied to mitochondrial disorders linked to dysfunctional complex-I.