Oxidative Phosphorylation Dysfunction Modifies the Cell Secretome

Abstract

Mitochondrial oxidative phosphorylation disorders are extremely heterogeneous conditions. Their clinical and genetic variability makes the identification of reliable and specific biomarkers very challenging. Until now, only a few studies have focused on the effect of a defective oxidative phosphorylation functioning on the cell's secretome, although it could be a promising approach for the identification and pre-selection of potential circulating biomarkers for mitochondrial diseases. Here, we review the insights obtained from secretome studies with regard to oxidative phosphorylation dysfunction, and the biomarkers that appear, so far, to be promising to identify mitochondrial diseases. We propose two new biomarkers to be taken into account in future diagnostic trials.

Keywords: biomarkers; fibroblast growth factor 21; growth differentiation factor 15; interleukine-6; mitochondrial DNA; mitochondrial diseases; oxidative phosphorylation system; secretome; vascular endothelial growth factor.

Figure 1

Oxidative phosphorylation (OXPHOS) system. OM, IMS, IM, and M code for mitochondrial outer membrane, intermembrane space, mitochondrial inner membrane, and mitochondrial matrix, respectively; ETC, electron transport chain; CI, CII, CIII, CIV, CV, and Cyt c, code for respiratory complexes I, II, III, IV, ATP synthase, and cytochrome c, respectively; Q, coenzyme Q₁₀; NADH and NAD⁺, reduced and oxidized forms of nicotinamide adenine dinucleotide; FADH₂ and FAD, reduced and oxidized forms of flavin adenine dinucleotide, H⁺, protons; e⁻, electrons; ATP, ADP, and Pi, adenosine triphosphate, adenosine diphosphate, and inorganic phosphate, respectively; H₂O, water; O₂, oxygen; ROS, reactive oxygen species. OXPHOS inhibitors: rotenone, capsaicin; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TTFA: thenoyltrifluoroacetone; antimycin A; NaCN: sodium cyanide; hydrogen sulfide; sodium azide; oligomycin; FCCP: carbonyl cyanide 4-[trifluoromethoxy] phenylhydrazone.

Figure 2

Cells or tissues affected by an OXPHOS dysfunction may modify their secretome, sending signaling molecules to other organs through the bloodstream and affecting their function. Such molecules could be detected and used as biomarkers for mitochondrial diseases.