Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes

Pooja Gupta, Sristi Chakroborty, Arun K. Rathod, K. Ranjith Kumar, Shreya Bhat, Suparna Ghosh, Pallavi Rao T, Kameshwari Yele, Raman Bakthisaran, R. Nagaraj, Moutusi Manna and Swasti Raychaudhuri ()
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Pooja Gupta: Uppal Road
Sristi Chakroborty: Uppal Road
Arun K. Rathod: Academy of Scientific and Innovative Research (AcSIR)
K. Ranjith Kumar: Uppal Road
Shreya Bhat: Uppal Road
Suparna Ghosh: Uppal Road
Pallavi Rao T: Uppal Road
Kameshwari Yele: Uppal Road
Raman Bakthisaran: Uppal Road
R. Nagaraj: Uppal Road
Moutusi Manna: Academy of Scientific and Innovative Research (AcSIR)
Swasti Raychaudhuri: Uppal Road

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Sequence evolution of protein complexes (PCs) is constrained by protein-protein interactions (PPIs). PPI-interfaces are predominantly conserved and hotspots for disease-related mutations. How do lipid-protein interactions (LPIs) constrain sequence evolution of membrane-PCs? We explore Respiratory Complexes (RCs) as a case study as these allow to compare sequence evolution in subunits exposed to both lipids in inner-mitochondrial membrane (IMM) and lipid-free aqueous matrix. We find that lipid-exposed surfaces of the IMM-subunits but not of the matrix subunits are populated with non-PPI disease-causing mutations signifying LPIs in stabilizing RCs. Further, IMM-subunits including their exposed surfaces show high intra-kingdom sequence conservation but remarkably diverge beyond. Molecular Dynamics simulation suggests contrasting LPIs of structurally superimposable but sequence-wise diverged IMM-exposed helices of Complex I (CI) subunit Ndufa1 from human and Arabidopsis depending on kingdom-specific unsaturation of cardiolipin fatty acyl chains. in cellulo assays consolidate inter-kingdom incompatibility of Ndufa1-helices due to the lipid-exposed amino acids. Plant-specific unsaturated fatty acids in human cells also trigger CI-instability. Taken together, we posit that altered LPIs calibrate sequence evolution at the IMM-arms of eukaryotic RCs.

Date: 2025
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DOI: 10.1038/s41467-025-57295-7

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