Obesity is the most significant risk factor for the development of atherosclerotic cardiovascular disease (CVD). The accumulation of excess fat mass directly affects cellular physiology to cause an imbalance in metabolic homeostasis  leading to insulin resistance (IR) which is the primary etiology of metabolic syndrome which includes hyperinsulinemia, type 2 diabetes mellitus, hypertension, hyperlipidemia, and an increased risk of atherosclerotic CVD. Recent evidence suggests that mitochondrial energetic dysfunction plays a role in the pathogenesis of obesity, IR, and CVD. Homeostasis of the mitochondrial proteome (proteostasis) directly impacts mitochondrial function and is negatively impacted by oxidative stress. Obesity and over-nutrition are known to increase oxidative radicals produced by the mitochondria. The overall hypothesis of this study is that increased oxidative stress in obesity inhibits mitochondrial proteostasis, particularly of the proteins required for mitochondrial respiration, which causes the mitochondrial dysfunction that causes metabolic syndrome. The enzyme methionine sulfoxide reductase A (MsrA) repairs oxidized methionine residues in proteins, prevents oxidation of other amino acids and prevents oxidation-induced protein misfolding. Thus, MsrA plays a crucial role in regulating cellular proteostasis. We find that overexpression of MsrA only in the mitochondria (mMsrA) in mice prevents obesity-induced insulin resistance. This study tests whether mMsrA prevents insulin resistance through enhanced mitochondrial proteostasis by addressing the following aims: Specific Aim 1 will test whether increasing mitochondrial MsrA attenuates obesity-induced mitochondria energetic dysfunction. Specific Aim 2 will test whether obesity-induced oxidation and misfolding of the mitochondrial proteome is prevented by mitochondrial MsrA. This proposal defines a novel mechanism with potential to be targeted to prevent the progression of IR and metabolic syndrome and thus reduce risk of CVD in at-risk patients.
|Program type||Beginning Grant-in-Aid|
|Effective start/end date||01/01/2015 → 12/31/2016|