Mitochondrial dysfunction: a basic mechanism in inflammation-related non-communicable diseases and therapeutic opportunities

Abstract

Obesity is not necessarily a predisposing factor for disease. It is the handling of fat and/or excessive energy intake that encompasses the linkage of inflammation, oxidation, and metabolism to the deleterious effects associated with the continuous excess of food ingestion. The roles of cytokines and insulin resistance in excessive energy intake have been studied extensively. Tobacco use and obesity accompanied by an unhealthy diet and physical inactivity are the main factors that underlie noncommunicable diseases. The implication is that the management of energy or food intake, which is the main role of mitochondria, is involved in the most common diseases. In this study, we highlight the importance of mitochondrial dysfunction in the mutual relationships between causative conditions. Mitochondria are highly dynamic organelles that fuse and divide in response to environmental stimuli, developmental status, and energy requirements. These organelles act to supply the cell with ATP and to synthesise key molecules in the processes of inflammation, oxidation, and metabolism. Therefore, energy sensors and management effectors are determinants in the course and development of diseases. Regulating mitochondrial function may require a multifaceted approach that includes drugs and plant-derived phenolic compounds with antioxidant and anti-inflammatory activities that improve mitochondrial biogenesis and act to modulate the AMPK/mTOR pathway.

Figure 1

Mutations in mitochondrial DNA are accompanied by different disease-suggestive phenotypes (myopathies, neuropathies, diabetes, and signs of reduced lifespan and premature aging). Severe mitochondrial dysfunction triggers a high level of oxidative and inflammatory damage, impairs tissue function, and promotes age-related diseases.

Figure 2

Clinically, it is evident that, in severe obesity, (a) the presence of liver steatosis may vary from more than 80% to less than 5% of patients. Conversely, in most obese patients with some degree of liver steatosis (b), this condition disappeared in a relatively brief period of time after significant weight loss due to bariatric surgery.

Figure 3

The mitochondrial matrix hosts the mitochondrial metabolic pathways (TAC cycle, β-oxidation, and haem synthesis), and the inner membrane contains the electron transport chain complexes and ATP synthase. Exchange carriers such as the malate-aspartate shuttle are also essential. Under caloric restriction, the mitochondrion achieves the highest efficiency, and high caloric intake produces dysfunction and a consequent increase in apoptosis, which promotes metabolic syndrome and age-related diseases.

Figure 4

Schematic and abridged representation of the multiple roles of mitochondria in cellular processes that are associated with the pathogenesis of the more prevalent diseases.

Figure 5

Mitochondrial fusion (a) and fission (b) processes in the liver (arrows). Mitochondrial morphology is basically controlled by metabolism and inflammation, and each change in morphology is mediated by large guanosine triphosphatases of the dynamin family, consistent with a model in which the capacity for oxidative phosphorylation is maximised under stressful conditions.

Figure 6

The complete elimination of mitochondria by autophagy (arrow) is a process linked to mitochondrial fission and fusion. Mitochondria also employ quality-control proteases to eliminate damaged molecules through the transcriptional induction of chaperones or the ubiquitin proteasome quality-control pathway.

Figure 7

The nutrient availability of food in “natural” conditions for mice is likely low and near the condition known as calorie restriction. In the laboratory, however, mice are usually fed ad libitum, and certain biases cannot be discarded. However, mitochondria from mice fed a chow diet (a) display rapid morphological changes when mice are fed with high-fat diets (b).

Figure 8

Activation of AMPK in macrophages promotes the switch from a proinflammatory to an anti-inflammatory phenotype by inducing a shift from glycolysis towards mitochondrial oxidative metabolism. In obesity, there may be a shift towards proinflammatory states, whereas in dietary restriction the balance may shift towards anti-inflammatory phenotypes through the activation of AMPK (a). The activation of AMPK implies the inhibition of mTOR, and several compounds are known to regulate this pathway (b). The inhibition of mTOR extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Several characterised inhibitors are already clinically approved, and others are under development.