TMEM65 found to support calcium clearance in cells, with implications spanning heart failure and Alzheimer’s pathology.
A team of scientists has identified a mitochondrial membrane protein – TMEM65 – as a key player in maintaining cellular calcium balance, with potentially wide-ranging implications for the treatment of cardiovascular and neurodegenerative diseases. The findings, published in Nature Metabolism, describe how TMEM65 regulates NCLX, the mitochondrial sodium-calcium exchanger, offering new insight into how disruptions in calcium handling contribute to age-related pathology [1].
Mitochondria are central to energy production and cell survival, but their function can be severely compromised when calcium accumulates to pathological levels. NCLX plays an essential role in maintaining calcium homeostasis within mitochondria by extruding calcium ions in exchange for sodium; however, little has been known about how this exchanger is regulated. According to the research team, the complexity of NCLX’s structure has historically impeded efforts to dissect its regulation.
“NCLX has a very complex structure, which has impeded the study of its regulation and hindered progress in therapeutic development,” Dr John W Elrod, lead author and professor in the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, said. “For our latest study, we decided to take a different approach, using biotin tagging, which allowed us to trace NCLX’s interactions with other proteins in intact cells [2].”
Longevity.Technology: This study sheds light on a long-elusive mechanism regulating mitochondrial calcium efflux – an emerging node of control in aging biology. By identifying TMEM65 as a direct activator of NCLX, the primary mitochondrial sodium-calcium exchanger, the research offers a clearer picture of how calcium dysregulation contributes to age-related dysfunction in the heart, brain and skeletal muscle [1]. The implications for geroscience are clear: TMEM65 overexpression protects against calcium-induced cell death, setting the stage for novel therapeutic strategies to stave off mitochondrial collapse in aging tissues.
While the findings are preclinical and focused on mouse models, they mark a strategically important advance. The application of proximity labeling to map the interactome of NCLX represents a powerful platform for future tissue-specific interventions. Still, caution is warranted. The complexity of mitochondrial calcium dynamics – and their entanglement with other hallmarks of aging – means that TMEM65 modulation must be studied carefully in diverse contexts, including human models. As researchers work toward safe, targeted modulation of this pathway, TMEM65 may emerge as a promising lever to shift the trajectory of aging at its metabolic core.
A link between mitochondrial dysfunction and disease
The team employed proximity biotinylation – an advanced proteomic technique that enables identification of proteins in the vicinity of a target protein in live cells – to screen for regulators of NCLX [1]. Among the interacting proteins discovered, TMEM65 stood out. While previously uncharacterised, TMEM65 is embedded in the mitochondrial membrane and emerged as a direct and functionally significant interactor of NCLX.
“TMEM65 was of particular interest because it is a mitochondrial protein of unknown function,” Elrod explained. “We also knew about a case report in which a young girl with a loss-of-function mutation in TMEM65 experienced profound muscle weakness and microcephaly (abnormally small head/brain) and neurological dysfunction [2].”
This clinical link prompted further investigation; using genetic models in mice, the researchers demonstrated that a deficiency of TMEM65 led to pronounced mitochondrial calcium overload, cell death, neuromuscular dysfunction and signs of premature aging. In contrast, overexpression of TMEM65 was protective – preserving mitochondrial integrity and cellular function under conditions of calcium stress [1].
These findings suggest that the TMEM65-NCLX complex plays a central role in safeguarding mitochondrial function during aging and disease. Since both cardiac and neuronal tissues are heavily reliant on mitochondrial efficiency, the therapeutic potential of targeting this complex may extend across multiple age-associated conditions.
Therapeutic implications for multiple diseases
“TMEM65 is a promising therapeutic target,” said Elrod. “Figuring out how to augment or otherwise alter its interaction with NCLX could offer an important treatment option for patients affected by diseases involving pathogenic calcium buildup in mitochondria.”
The research holds particular relevance for conditions such as heart failure and Alzheimer’s disease, both of which are known to involve mitochondrial dysfunction and impaired calcium handling. In murine models, alterations in TMEM65 expression impacted markers of cardiac function and neurodegeneration, further highlighting its systemic relevance.
Amy J Goldberg, MD, FACS, The Marjorie Joy Katz Dean of the Lewis Katz School of Medicine, emphasized the broader importance of the findings. “This discovery exemplifies the transformative science happening at the Lewis Katz School of Medicine,” she said. “By deepening our understanding of mitochondrial function, our researchers are paving the way for innovative treatments that could have a profound impact on patients with heart failure, Alzheimer’s disease, and beyond.”
Looking ahead
While the study offers a clear mechanistic foundation, further research is required to evaluate the safety and efficacy of TMEM65-based therapies. Questions remain about how this pathway behaves across different tissues and disease states in humans, and how pharmacological modulation might be achieved without disturbing essential ion gradients.
Nonetheless, the identification of TMEM65 as a regulator of mitochondrial calcium efflux represents a significant step in elucidating the molecular architecture of aging and disease. As researchers continue to unravel the cellular choreography of calcium regulation, this discovery could help inform a new class of interventions targeting mitochondrial resilience in the face of age-related stress.
Photograph: iLexx-Envato
[1] https://www.nature.com/articles/s42255-025-01250-9[2] https://medicine.temple.edu/discovery-mitochondrial-protein-opens-path-therapeutic-advances-heart-alzheimers-disease
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