Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects

Abstract

Background: Mitochondrial dysfunction is implicated in the pathogenesis of Type 2 diabetes (T2D) and the development of diabetes related complications such as cardiovascular disease and stroke. Mitochondria produce several small polypeptides that may influence mitochondrial function and may impact on insulin sensitivity, such as humanin (HN) and the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) that are mitochondrial derived proteins (MDP). The aim of this study was to determine MDP in normal, prediabetes and diabetes subjects. Subjects and Measurements: In this cross-sectional study, we analyzed the serum concentrations of MDP and adiponectin (ADP) in 225 subjects: normal ( n = 68), pre-diabetes ( n = 33), T2D less than (good control; n = 31), and greater than HbA1c 7% (poor control; n = 93) subjects. The relationship of serum MDP and ADP concentrations with biochemical and anthropometric measurements were performed and assessed by multilinear regression. Results: Serum HN concentrations were lower in T2D ( p < 0.0001) and negatively correlated with age ( p < 0.0001), HbA1c ( p < 0.0001), glucose ( p < 0.0001), triglycerides ( p < 0.003), ALT ( p < 0.004), and TG/HDL ratio ( p < 0.001). Circulating HN levels were positively correlated to cholesterol ( p < 0.017), LDL ( p < 0.001), and HDL ( p < 0.001). Linear regression analysis showed that HbA1c and ALT were two independent predictors of circulating HN. Similarly, serum MOTS-c was significantly lower in T2D subjects compared to controls ( p < 0.007). Circulating MOTS-c positively correlated with BMI ( p < 0.035), total cholesterol ( p < 0.0001), and LDL ( p < 0.001) and negatively correlated with age ( p < 0.002), HbA1c ( p < 0.001), and glucose ( p < 0.002). Serum ADP concentrations were lower in T2D ( p < 0.002) and negatively correlated with HbA1c ( p < 0.001), weight ( p < 0.032) TG ( p < 0.0001), and ALT ( p < 0.0001); and positively correlated with HDL ( p < 0.0001) and HN ( p < 0.003). Linear regression analysis showed that HbA1c and weight were two independent predictors of circulating ADP. Multilinear regression showed that HN and MOT-c correlated with each other, and only HN correlated with HbA1c. Conclusion: The MDPs HN and MOT-c, similar to ADP, are decreased in T2D and correlate with HbA1c. The data provide a...

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan

“…In this study, midlife humanin treatment attenuated the obesity that occurs in mid-life, but did not exacerbate the gradual decline in bodyweight at older ages. This improvement in metabolic parameters has been previously seen in mice treated with HNG and in fact, human studies have found that HN levels were negatively correlated with HbA1c levels and triglyceride levels [29,44]. Taken together, even at the low doses that we administered to middleaged mice, humanin treatment improved several lifespan and healthspan markers such as metabolism, fibrosis, and cognitive decline [41,68].…”

“…Circulating levels of humanin correlate with lifespan in different mouse models of aging and bi-weekly injections of the humanin analogue HN-S14G delays the cognitive decline in mice [39][40][41][42]. Another MDP, MOTS-c, has already been associated with longevity in centenarians [43], although association studies of humanin levels in humans have been equivocal [44][45][46]. In this study we further investigated the relationship between humanin, longevity, and healthspan using transgenic worms, multiple mammalian species with divergent lifespans, and also the children of centenarians compared to age-matched controls.…”

Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition

“…While MOTS-c serum levels have recently been reported to negatively correlate with age in a cohort of participants with type 2 diabetes [32], interpretation of this data is confounded by the healthy control group being significantly younger than the diabetic groups. Regardless, our results support this finding and previous observations of lower MOTS-c plasma levels in aged mice, but are in contrast to reported murine skeletal muscle age-associated decline in MOTS-c levels [14].…”

“…However, when the ability of the muscle cell to tolerate or adapt to this stress is overwhelmed then MOTS-c levels may decrease along with function of the cell. In support, some studies have reported reduced plasma levels of MOTS-c in people with obesity, type 2 diabetes [32,37] or impaired coronary endothelial function [38], and exogenous MOTS-c treatment restores skeletal muscle insulin sensitivity in mice [14,27].…”

MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

“…It is possible that the exported MOTS‐c transcript may be cotranslated and translocated to the mitochondria using such mitochondrial‐associated cytoplasmic ribosomes. Work is also in progress to understand cellular cues that induce MOTS‐c expression, and metabolic alterations and inflammation may be key. Similar to HN, MOTS‐c has both intracellular and endocrine roles .…”