Deciphering the role of TMEM65 and NCLX-Mediated Mitochondrial Calcium Export in Cancer

• Applicant: Professor Dr. Ivan Bogeski
• Subject Area: Anatomy and Physiology ; Biophysics ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560963311

Mitochondria are not only the powerhouses of cells but also act as a major calcium (Ca²⁺) signaling hub, linking Ca²⁺ dynamics to vital cellular functions, as well as to carcinogenesis and resistance to cancer therapies. Calcium enters mitochondria primarily through the mitochondrial Ca2+ uniporter (MCU) complex, while its efflux is mediated by the mitochondrial Na+/Ca2+/Li+ exchanger (NCLX) and the recently identified TMEM65 protein. Additionally, the Ca2+/H+ antiporters TMBIM5 and LETM1 are known to participate in mitochondrial Ca2+ (mCa2+) efflux. A tightly coordinated balance between mCa2+ import and export is crucial for proper mitochondrial function, cellular metabolic activity, and general cell biology. While the role of mCa²⁺ import through the MCU complex has been extensively studied in the context of cancer, the mechanisms of mCa²⁺ export remain less understood. Recently, TMEM65 has emerged as an essential positive regulator of mCa²⁺ export. However, the mechanisms of its functional regulation, the possible interaction of TMEM65 with other Ca2+-transporting proteins and its potential role in cancer are not understood. Building on our (Bogeski and Sekler) combined expertise and research interests, we propose a collaborative effort to study TMEM65, its regulation of mCa2+ export, and the functional significance of TMEM65-NCLX interplay in cancer biology. Specifically, we aim to investigate common mechanisms of mCa2+ export regulation in two distinct cancer models: melanoma and pancreatic ductal adenocarcinoma (PDAC). To achieve this, we will: 1) Dissect the role of TMEM65 in shaping mitochondrial and cellular Ca2+ signals, 2) Characterize the contribution of TMEM65 and NCLX on cancer pathobiology and therapeutic sensitivity and 3) Identify molecular determinants and protein interactions linking TMEM65 and NCLX with cancer cell aggressive behavior. Our long-term goal is to provide mechanistic insights into the roles of TMEM65 and NCLX in the regulation of mCa2+ homeostasis, examine their contribution to carcinogenesis, and unravel their potential as molecular targets for anti-cancer therapies.

• DFG Programme: Research Grants
• International Connection: Israel
• Partner Organisation: The Israel Science Foundation
• Cooperation Partner: Professor Dr. Israel Sekler