Introduction
Obesity is associated with oxidative stress, which can result in mitochondrial damage and a defect in mitochondrial biogenesis.1–6 Triggers, such as hyperglycemia, can induce increased intracellular reactive oxygen species (ROS).1–7 Surprisingly, bariatric surgery-induced weight loss has been shown to improve mitochondrial biogenesis, whereas diet-induced weight reduction did not improve mitochondrial dysfunction.4 Moreover, bariatric surgery may be associated with improved renal tubular injury, which is determined via monitoring the level of kidney injury molecule-1 in patients with obesity.8 This finding may account for the additional benefits experienced by patients after bariatric surgery, independent of weight reduction. For example, bariatric surgery in patients with obesity involves weight-independent glucose-lowering effects, and is thus considered to be a highly effective method for preventing, or resolving, type 2 diabetes mellitus (T2DM), regardless of the patient’s T2DM status prior to surgery.9 10 Numerous studies have also reported that bariatric surgery is superior for improving glycemic and metabolic variables compared with non-surgical treatments in patients with obesity with T2DM.10 11 A Danish study further showed that individuals with obesity with T2DM had a 47% lower risk of microvascular complications after bariatric surgery compared with that of patients that did not receive the surgery.11 In addition, bariatric surgery significantly reduced genomic damage in an obese rat model.12 However, the underlying mechanism remains unclear, and despite the known link between mitochondrial damage and obesity, the influence of bariatric surgery on changes to cell-free mitochondrial DNA (mtDNA) in patients with obesity with T2DM has not been established.
Mitochondria contain their own DNA genome1; thus, the mtDNA copy number can reflect the degree of mitochondrial damage. The cell-free mtDNA copy number has been explored as an easily accessible and non-invasive biomarker for the detection of mitochondrial dysfunction,13 14 which is generally measured as the mitochondrial-to-nuclear genome ratio (Mt/N).1 The intracellular and extracellular mtDNA levels have been suggested as associated with various clinical outcomes.2 3 15 Cell-free mtDNA is reportedly derived from injured tissue or cells in the body.16 Specifically, urinary cell-free mtDNA content has been most widely evaluated in various clinical settings as a non-invasive biomarker, of which increased levels can effectively predict poor outcomes in patients with T2DM, acute kidney injury and diabetic nephropathy.15
We previously observed decreased urinary mtDNA levels after bariatric surgery in patients with obesity and without diabetes.17 In addition, the intracellular mtDNA copy number recovered in patients with obesity after weight reduction surgery, reaching the level of non-obese control subjects.18 However, since T2DM induces higher degrees of mitochondrial dysfunction in patients with obesity,4 18 the extracellular mtDNA copy number in patients with obesity with T2DM may differ from that of patients without diabetes.
Thus, the aim of the present study was to explore the change in cell-free serum and urine mtDNA copy numbers in patients with morbid obesity with, and without, T2DM before, and after, bariatric surgery as a surrogate for mitochondrial dysfunction, and the levels were compared with those of healthy volunteers (HV) as a control group.