Medizinische Universität Graz - Research portal
Selected Publication:
Lederer, S.
The impact of different mitochondrial Ca2+ modulators on lifespan and health of C. elegans.
[ Diplomarbeit/Master Thesis (UNI) ] Universität Graz; 2024. pp.43.
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- Authors Med Uni Graz:
- Advisor:
- Madreiter-Sokolowski Corina
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- Abstract:
- Aging is a highly complex and poorly understood process that makes the body vulnerable to age-related diseases such as cardiovascular and neurodegenerative diseases. As we live in an increasingly aging society, it is crucial to understand the molecular mechanisms behind aging and to find new therapeutic approaches to intervene and delay aging and associated diseases. Mitochondria are crucial to cellular metabolism as they are the production site of ATP and reactive oxygen species (ROS) and can trigger apoptosis. Calcium (Ca2+) is a key regulator of mitochondrial function and is able to enter the mitochondrial matrix through the mitochondrial Ca2+ ([Ca2+]mito) transporter (MCU). However, aging is often associated with mitochondrial dysfunction caused by disturbances in ROS, and Ca2+ homeostasis. We therefore set out to investigate how modulation of [Ca2+]mito homeostasis during aging affects life- and health span in the model organism Caenorhabditis elegans (C. elegans). In this study, we used lifespan analyses, [Ca2+]mito measurements, and motility assays to answer these questions. To modulate the Ca2+ homeostasis, we induced mcu-1 knockdown to the worms and used pharmacological inhibitors of the MCU complex, such as the anti-cancer drug mitoxantrone and the small molecule MCU-i11. Ca2+ measurements from mcu-1 worms revealed reduced basal [Ca2+]mito concentrations and matrix Ca2+ uptake compared to wild type worms. Lifespan analyses have shown that the knockdown of mcu-1 and its inhibition by treatment with mitoxantrone leads to an extension of the lifespan of C. elegans. Also, mcu-1 knockdown and mitoxantrone treatment led to increased motility in old age, thereby extending health span. The second MCU inhibitor, MCU-i11, improved survival in middle-age but had no effect on life expectancy in old age. Motility assays showed a similar result, with increased worm activity only present in middle-age. We suspect that the inhibitor is unable to prevent Ca2+ influx during high Ca2+ concentrations in old age. Based on the results of MCU knockdown and inhibition by mitoxantrone, we conclude that the impaired Ca2+ conditions in early life mechanisms might be related to longevity.