Pro-longevity natural compounds as suppressors of mitochondrial complex I associated diseases

• Applicant: Privatdozentin Natascia Ventura, Ph.D.
• Subject Area: Biogerontology and Geriatric Medicine ; Experimental Models for the Understanding of Nervous System Diseases ; Toxicology, Laboratory Medicine
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269345411

Over the last few decades, mitochondrial dysfunction, ascribed to mutations in either mitochondrial DNA or nuclear DNA, has been established as a cause for numerous neuro-metabolic developmental disorders. Unfortunately most of these diseases are life-threatening and do not have effective cures thus imposing an urgent need to develop appropriate disease models and tools to advance our understanding of disease pathogenesis and search for targeted therapeutics. Dietary interventions may especially provide more malleable and feasible therapeutic approaches than genetic interventions. Thanks to my first DFG grant we extensively characterized bimodal adaption responses to mitochondrial stress at phenotypic, metabolic and molecular levels, with special focus on animal neuronal and mitochondrial changes. Exploiting the very reproducible and discrete animal phenotypes arising from different degrees of mitochondrial stress, we established an automated microscopy platform for high content screening to identify interventions acting through mitochondria. We also developed different C. elegans models for mitochondrial disorders and focused on models of Leigh’s Syndrome associated with Complex I deficiency: we extensively characterized animals’ mitochondrial and neuronal alterations and identified Lutein as a potential disease suppressor. To follow up on these findings, the overall aim of this renewal proposal is to exploit our C. elegans models for Complex I deficiency to characterize mode of action of Lutein and to search for novel possible diseases suppressors. Our goal will be achieved following three distinct but interrelated objectives, which uses complementary model systems and state of the art methodologies:1) To unravel mode of action of Lutein protective effects in C. elegans2) To validate Lutein protective effects in mammalian disease models3) To identify suppressors of other Complex I-associated disease in C. elegansBased on our findings we will specifically unravel the activity of Lutein on synaptic functionality and validate it mammalian neuronal systems. Moreover, we will test Lutein rescuing effect on other Complex I deficient C. elegans models and will assess the hypothesis that other pro-longevity natural compounds may indeed act as diseases suppressors. Our project is expected to suggest novel therapeutics for future testing in additional mammalian models and eventually humans, which could lead to treatment of otherwise non-curable disorders. We envision such a screening approach to be suitable and convenient to identify novel therapeutics potentially beneficial for both rare and common diseases ascribed to mitochondrial dysfunction. Results obtained with this study will thus directly impact on basic research, but will also eventually have repercussion on human health and healthcare system.

• DFG Programme: Research Grants