Fig. 5: Structural impact of non-synonymous CI gene mutations. | Nature Communications

Fig. 5: Structural impact of non-synonymous CI gene mutations.

From: OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

Fig. 5

a List of malignant samples carrying non-synonymous variants with HP levels ≥30% (HP% = heteroplasmy levels, Gene=mt-gene, mt-pos=location of variant on mtDNA sequence, Ref= nucleotide in rCRS sequence, Mut=altered nucleotide found in sample, AA-pos=position of encoded amino acid in protein sequence, Ref=amino-acid in wild-type protein, Mut=altered amino acid). b Structure of human respiratory Complex I and location of mutations found in this study. mtDNA-encoded CI-subunits (ND1-6) are shown in colors (ND1 = dark red, ND2 = light blue, ND3 = orange, ND4 = red, ND4L = purple, ND5 = dark blue and ND6 = light blue), mutations are shown as black circles and Fe-S clusters as yellow spheres. To visualize mutation sites see complemental iSee package using any JavaScript enabled web browser ([https://github.com/genepi/mt-c1]). c Structural change caused by the F411S mutation (red circle) in ND4. Wild-type (F) and mutated variant (S) amino acids are depicted and superimposed together with amino-acid residues involved in the hydrophobic interaction network of the α-helix structure (W359, L360, and W416, respectively). d Structural change caused by the T387A mutation located within the loop of the discontinuing helix 12 in the central axis of CI membrane domain (blue circle) in ND5. Wild-type (T) and mutated variant (A) are superimposed and the stabilizing hydrogen bond present in the wild-type protein is depicted by a scattered line. e–f HRR traces of the malignant biopsies carrying the F411S (e) or the T387A mutation (f), respectively. The red line represents wet mass-specific O2 flux (oxygen consumption (pmol s−1 mg−1]). g–h Respiratory capacities of malignant samples (red) carrying either the F411S mutation (g) or the T387A mutation (h), compared to the corresponding benign tissue (blue). Values represent mean ± SD of the two separate measurements for each tissue sample. See Fig. 2 and Supplementary Tables 1–2 for abbreviations, coupling states and SUIT protocol.

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