Journal of Molecular Biology · Jun 18, 2026

An Evolutionarily Conserved TUSC2-OSCP Interface Suggests a Mitochondrial Ca²⁺-Sensing Mechanism for ATP Synthase Regulation

By Ivanov SV, Uzhachenko RV, Boudko SP et al.

Mitochondrial ATP synthase (mATPS) has the capacity to regulate the permeability transition pore (mPTP) during Ca²⁺ fluctuations. Dysregulation of this mechanism is implicated in neurodegenerative and other diseases; however, the endogenous mechanisms that couple calcium sensing to mATPS function remain poorly defined. We recently demonstrated that loss of TUSC2, a mitochondrial Ca²⁺-binding protein, leads to mitochondrial Ca²⁺ overload and sustained mPTP opening. The oligomycin sensitivity-conferring protein (OSCP), a regulatory subunit of mATPS, responds to Ca²⁺ and oxidative stress, positioning it as a potential integrator of bioenergetic and stress signals. With age, the ability of OSCP to maintain regulatory interactions and resist stress-induced conformational perturbations declines, contributing to multiple pathologies. Here, we combine AI-assisted structural modeling with phylogenetic analysis to nominate TUSC2 as a previously unrecognized candidate OSCP-interacting partner. Across evolution-from basal eukaryotes to higher metazoans-TUSC2 exhibits near-invariant conservation of its central Ca²⁺-binding motif (CBM), in contrast to pronounced divergence of its N-terminal region. AlphaFold3 modeling provides a structural framework for this conservation, predicting Ca²⁺-dependent engagement of the CBM with a conserved C-terminal region of OSCP with established regulatory function. The predicted interface is preserved across phylogenetically distant species, indicating co-conservation of interacting surfaces. The model further suggests coordinated engagement of Ca²⁺ and a second metal ion by TUSC2 and OSCP, as well as accommodation of a nucleotide. The deep conservation of these features across eukaryotes is consistent with a functionally constrained, Ca²⁺-sensing regulatory role for TUSC2 in mATPS function, with potential implications for mPTP regulation.

doi.org/10.1016/j.jmb.2026.169911Open accessPubMed 42314984Mechanisms