A mitochondrial proteome profile indicative of type 2 diabetes mellitus in skeletal muscles

Abstract

The pathogenesis of type 2 diabetes mellitus (T2DM) is closely associated with mitochondrial functions in insulin-responsive tissues. The mitochondrial proteome, compared with the mitochondrial genome, which only contains 37 genes in humans, can provide more comprehensive information for thousands of mitochondrial proteins regarding T2DM-associated mitochondrial functions. However, T2DM-associated protein signatures in insulin-responsive tissues are still unclear. Here, we performed extensive proteome profiling of mitochondria from skeletal muscles in nine T2DM patients and nine nondiabetic controls. A comparison of the mitochondrial proteomes identified 335 differentially expressed proteins (DEPs) between T2DM and nondiabetic samples. Functional and network analyses of the DEPs showed that mitochondrial metabolic processes were downregulated and mitochondria-associated ER membrane (MAM) processes were upregulated. Of the DEPs, we selected two (NDUFS3 and COX2) for downregulated oxidative phosphorylation and three (CALR, SORT, and RAB1A) for upregulated calcium and protein transport as representative mitochondrial and MAM processes, respectively, and then confirmed their differential expression in independent mouse and human samples. Therefore, we propose that these five proteins be used as a potential protein profile that is indicative of the dysregulation of mitochondrial functions in T2DM, representing downregulated oxidative phosphorylation and upregulated MAM functions.

Serum biomarkers from cell-based assays for AhRL and MIS strongly predicted the future development of diabetes in a large community-based prospective study in Korea

“…Other experimental evidence also supports the hypothesis that dioxins impair β-cell function 39,40 or induces vascular inflammation 41 in mice. Proteomic analysis of mitochondria from skeletal muscles of diabetes patients showed that subunits of oxidative phosphorylation were downregulated 42 . Transcriptome profiling revealed that a number of genes responsible for mitochondria ATP synthesis, oxidative phosphorylation, or mitochondrial dynamics were downregulated in human diabetes islets or β-cells 43,44 .…”

The Mitochondrial Proteomic Signatures of Human Skeletal Muscle Linked to Insulin Resistance

“…Among the 335 differentially regulated mitochondrial proteins, 135 proteins were upregulated in T2D compared with the nondiabetic controls, whereas 200 proteins were downregulated (Figure 3). The proteins upregulated in patients with T2D were mainly involved in processes related to molecular transport and cytoskeletal organization, while Chae et al showed a significant downregulation of several proteins in metabolic pathways, including the TCA cycle, fatty acid oxidation, and glycolysis, and in T2D patients [117]. Interestingly, OXPHOS proteins were represented both among the upregulated and downregulated proteins (6 and 16 proteins, respectively), suggesting an overall altered metabolic activity in patients with T2D, when compared to healthy individuals.…”

“…In a more recent study [117], Chae et al published the, so far, most comprehensive mitochondrial proteome of human skeletal muscle. Chae and co-authors implemented ultra-high-pressure nano-LC-ESI-MS/MS on isolated mitochondria from skeletal muscle of T2D patients and non-diabetic control individuals and identified 1671 proteins in at least half of the 10 samples [117]. Of these proteins, 1150 mitochondrial proteins (69%) were represented by two or more peptides (Figure 2).…”

“…The technical advances that have occurred in recent years within the field of MS-based proteomics are particularly evident in the latest attempt to characterize the mitochondrial proteome in skeletal muscle of patients with T2D. As mentioned above, Chae and co-authors used HPLC-ESI-MS/MS on isolated mitochondria from skeletal muscle of patients with T2D and non-diabetic controls and identified a total of 1150 mitochondrial proteins that were represented by two or more peptides and which were therefore selected for subsequent analysis [117]. Among the 335 differentially regulated mitochondrial proteins, 135 proteins were upregulated in T2D compared with the nondiabetic controls, whereas 200 proteins were downregulated (Figure 3).…”

Peer Review #1 of "Mitochondrial destiny in type 2 diabetes: the effects of oxidative stress on the dynamics and biogenesis of mitochondria (v0.1)"

“…Also the authors established that complex IV (CIV) is a common target for the mitochondrial remodelling induced by ageing or type 2 diabetes [76]. The study of proteomic profiles provides unique information about thousands of mitochondrial proteins that can be used to assess mitochondrial functions that are related to the development of type 2 diabetes [78]. The large size of the proteome indicates that many metabolic and cellular pathways are active in mitochondria.…”