Complex Metabolic Diseases and Mitochondria

Age-related metabolic diseases have increased to epidemic proportions in all industrialized countries. Aging is the most universal contributor to the aetiologies of metabolic decline and related diseases, including type 2 diabetes mellitus, cardiovascular disease, non-alcoholic steatohepatitis (NASH), stroke, neurodegenerative diseases, and cancer. According to observational studies, obesity is a major determinant of premature mortality and a risk factor for leading causes of death. Diabetes has increased dramatically over the past century, registering of 371 million cases worldwide in 2012. The prevalence of diabetes mellitus and glucose intolerance increases significantly with age.

Mitochondrial dysfunction has been reported in complex age-related diseases, as well as in aging itself. These observations thus support the notion that mitochondrial dysfunction and the accumulation of oxidative damage contribute to the pathogenesis of these diseases. Aging is characterised by the accumulation of mutations in mitochondrial DNA, which may be responsible for the alterations detected in this condition. In addition, the deregulation of various signalling pathways can induce mitochondrial dysfunction. The regulatory network that governs mitochondrial homeostasis may therefore be involved in the development of age-related conditions.

We have shown that mitochondrial morphology determines the function of these organelles. Mitochondrial architecture is determined by motility, fusion, and fission events. Mitochondrial fusion is mediated by mitofusins (Mfn1 and Mfn2, located in the outer mitochondrial membrane) and optic atrophy gene 1 (Opa1, located in the inner membrane), while mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), mitochondrial fission factor (Mff, located in the outer mitochondrial membrane), and fission 1 protein (Fis1, located in the outer mitochondrial membrane), among others.

Some of the proteins involved in mitochondrial dynamics are subject to exquisite control. In this regard, we have reported that the expression of Mfn2 is highly regulated in response to enhanced energy expenditure and exercise. Mfn2 is repressed in the muscle of obese or type 2 diabetic patients. The nuclear co-activators PGC-1alpha, and PGC-1beta activate Mfn2 gene transcription through ERRalpha and may participate in the changes in the expression of this gene. OPA1 and mitochondrial elongation are enhanced by insulin in cardiomyocytes.

In addition, we have reported that some proteins involved in mitochondrial fusion modulate metabolism in vivo. Mnf2 deficiency enhances proton leakage and reduces respiration, independently of changes in mitochondrial mass. Mfn2 ablation also alters glucose metabolism and energy expenditure. Liver-specific ablation of Mfn2 in mice leads to glucose intolerance and enhanced hepatic gluconeogenesis, whereas ablation in muscle causes higher susceptibility to glucose intolerance and insulin resistance in response to a high fat diet. Hypothalamic POMC neuron-specific ablation of Mfn2 results in hyperphagia, reduced energy expenditure, and obesity. OMA1 (an Opa1 protease) knockout mice are also obese as a result of deficient brown adipose tissue metabolism.

As to the mechanisms controlled by Mfn2, this protein regulates endoplasmic reticulum (ER) morphology, and the transfer of calcium from the ER to the mitochondria. We have also demonstrated that Mfn2 deficiency causes a chronic Unfolded Protein Response (UPR), which is crucial in the metabolic alterations associated with this condition.

Mitochondrial dynamics also plays a key regulatory role in determining the fate of mitochondria, namely whether they undergo degradation via selective autophagy.