Muscle OXPHOS and Nutrient Homeostasis

Prior treatment

• Diabetes (HgbA1c \> 6.4%) and/or taking insulin or other anti-diabetic drug therapy within the 4 weeks prior to enrollment.
• Use of any lipid-lowering medication (excluding nutritional supplements) within the 4 weeks prior to enrollment.
• Receiving treatment for a medical condition requiring chronic use of systemic (oral or parenteral steroids, except for the use of \< 5 mg prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only.
• Use of any investigational agents within 4 weeks of enrollment.

Other illness

• For all study groups (i.e., mitochondrial disease, normal weight, obese):
• Individuals who have a pacemaker, metal implants, claustrophobia, have worked around a metal grinder or a construction site, or that have known medical conditions which can be exacerbated by stress such as anxiety or panic attacks. Inability to lie flat in the MRI scanner for 90 minutes is also an exclusion criterion.
  • In addition, specific exclusion criteria for undergoing MRI scanning include:
  • ANY intra-luminal implant, filter, stent or valve replacement
  • ANY type of life assist device, pump, or prosthetic
  • ANY vascular clip or clamp
  • ANY surgically placed clips or clamps or bands on visceral organs
  • ANY intracranial implants of any type other than dental fillings
  • ANY non-removable piercings, jewelry, or medicinal patch
  • ANY personal history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic examination.
  • ANY personal history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation.
• Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.

Lab values

• Kidney disease. Estimated glomerular filtration rate \< 60 ml/min/1.73 m2 (calculated using the subject's measure serum creatinine and the Modification of Diet in Renal Disease \[MDRD\] study estimation formula).
• Liver disease. Persistent elevation of liver function tests at the time of study entry. Persistent SGOT (AST), SGPT (ALT), Alk Phos or total bilirubin, with values \> 3 times normal upper limits, will exclude a subject from study participation.
• Severe co-existing cardiac disease, characterized by any one of these self-reported conditions:
  • recent myocardial infarction (within the past 6 months).
  • evidence of ischemia on functional cardiac exam within the last year
  • left ventricular ejection fraction \< 30%.
• Anemia (baseline hemoglobin concentration \< 11 g/dl in women and \<12 g/dl in men), lymphopenia, (\< 1,000/µL), neutropenia (\< 1,500/µL), or thrombocytopenia (platelets \< 100,000/µL).
• Any known coagulopathy (including Factor V deficiency) or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) (low-dose aspirin treatment is allowed) or patients with an INR \> 1.5.

Other

• Any contraindication to MRI study (e.g., implanted non-compatible device, pacemaker, known claustrophobia).
• Acute or chronic pancreatitis.
• For female participants: Positive pregnancy test.
• Known active alcohol or substance abuse, including known tobacco use.
• Inability to fast comfortably for 10 hours (i.e., overnight).

• Indvidiuals who meet all of the following criteria are eligible for participation in the study:
• Male and female patients age 18 to 65 years of age.
• Ability to provide written informed consent.
• Cognitively and medically stable and able to comply with the procedures of the study protocol.
  • For individuals with mitochondrial disease:
  • Clinical history consistent with the diagnosis of mitochondrial disease, and molecular genetic diagnosis. To ensure consistency with other trials performed in mitochondrial disease, investigators will also ensure that participants meet the same set of previously published criteria. These include clinical features consistent with primary mitochondrial disease and molecular genetic proof of a pathogenic mutation in mtDNA or nDNA in a gene known to be associated with dysfunction of complexes I-V of the respiratory chain. Specifically, eligible participants must have defined mtDNA or nDNA mutations affecting subunits or assembly of these complexes that are associated with known clinical/pathological features, such as chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), mitochondrial encephalopathy and ragged red fibers (MERRF), neuropathy, ataxia and retinitis pigmentosa (NARP) or Leigh syndrome (45). Investigators will explicitly include individuals with Friedreich's Ataxia (46), a mutation in the mitochondrial protein frataxin, and those with mutations in respiratory chain complex II protein, succinate dehydrogenase (SDH).
  • For normal weight participants:
  • BMI \< 25 kg/m2. These will be matched with subjects with mitochondrial disease by age, sex, estrogen status (women), and usual self-reported physical activity (as either sedentary or not, i.e., for sedentary, less than 30 minutes of moderate physical activity 5 days per week, or vigorous physical activity for 20 minutes 3 days per week).
  • For obese participants:
  • BMI \> 30 kg/m2. These will be matched with subjects with mitochondrial disease by age, sex, estrogen status (women), and usual self-reported physical activity (as either sedentary or not, i.e., for sedentary, less than 30 minutes of moderate physical activity 5 days per week, or vigorous physical activity for 20 minutes 3 days per week).