Trifunovic, Aleksandra | Riemer, Jan - C 13 (TP)

Mitochondrial dysfunction is central to metabolic diseases such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). Among mitochondrial defects, Complex I (NADH:ubiquinone oxidoreductase) deficiency is common and closely associated with redox imbalance and impaired energy metabolism. However, the mechanisms that safeguard Complex I integrity under physiological and pathological conditions remain poorly understood.

This project addresses this gap by focusing on a conserved accessory subunit of Complex I that we propose functions as a redox-sensitive sensor of mitochondrial stress and a regulator of Complex I turnover and repair. Although mutations in this subunit have been linked to severe mitochondrial disorders such as Leigh syndrome, its contribution to chronic metabolic disease has not been explored. Our preliminary data identify key redox-sensitive residues within this protein, which will be targeted by site-specific mutagenesis.

The resulting variants will be analyzed in vitro and in vivo to determine their impact on Complex I dynamics. In addition, a knock-in mouse model carrying a redox-insensitive variant will be used to investigate mitochondrial turnover and adaptive responses in metabolic tissues under basal conditions and following high-fat diet challenge. By elucidating how redox signals regulate Complex I proteostasis, this work will provide new insights into mitochondrial resilience in health and disease. As mitochondrial turnover emerges as a promising therapeutic target, defining the role of this redox-responsive Complex I subunit may reveal novel strategies to restore mitochondrial function in metabolic disorders characterized by oxidative stress and respiratory dysfunction.

Mitochondrial dysfunction plays a key role in metabolic diseases such as type 2 diabetes, obesity, and NAFLD, with Complex I defects being among the most common. These defects disrupt redox balance, reduce ATP production, and promote oxidative stress. However, how Complex I integrity is maintained under stress remains poorly understood. This project aims to uncover the mechanisms regulating Complex I turnover, focusing on an accessory subunit we propose acts as a redox-sensitive regulator of mitochondrial proteostasis.

This project benefits from the complementary expertise of two leading research groups. Jan Riemer is an expert in redox biology and mitochondrial protein biochemistry, with a strong record in dissecting redox sensitive pathways. His lab offers advanced tools for analysing redox modifications and protein interactions with high precision. Aleksandra Trifunovic’s lab focuses on the physiological impact of mitochondrial dysfunction in health and disease. Using biochemical, in vivo, and physiological approaches, her group explores how mitochondrial quality control affects metabolism, lipid handling, inflammation, and organ homeostasis. Together, these teams will bridge mechanistic and physiological insights, linking redox regulated turnover of Complex I, to systemic metabolic responses. 

We will jointly generate and analyse in vivo and in vitro models expressing redox-insensitive protein variants, allowing us to examine how redox cues affect mitochondrial function under basal and stress conditions. This interdisciplinary collaboration ensures a multi-scale understanding, from molecular mechanisms to organismal physiology, enhancing both the scientific depth and translational impact of the project.