Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases?

Abstract

Mitochondrial damage is implicated as a major contributing factor for a number of noncommunicable chronic diseases such as cardiovascular diseases, cancer, obesity, and insulin resistance/type 2 diabetes. Here, we discuss the role of mitochondria in maintaining cellular and whole-organism homeostasis, the mechanisms that promote mitochondrial dysfunction, and the role of this phenomenon in noncommunicable chronic diseases. We also review the state of the art regarding the preclinical evidence associated with the regulation of mitochondrial function and the development of current mitochondria-targeted therapeutics to treat noncommunicable chronic diseases. Finally, we give an integrated vision of how mitochondrial damage is implicated in these metabolic diseases.

Keywords: mitochondria; cancer; cardiovascular diseases; insulin resistance; obesity.

Graphical Abstract

Figure 1.

Mitochondrial plasticity regulates the mitochondrial quality control and function. A mitochondrion is a malleable organelle that constantly changes its structure and shape to adapt its function and allow the normal replacement of anomalous mitochondria. (A) Mitochondrial fission is regulated by Drp-1, which binds to outer mitochondrial membrane (OMM) protein adaptor like Mff, which together with the endoplasmic reticulum, (ER) constrict and isolate the impaired mitochondria. On the other hand, mitochondrial fusion (B) is orchestrated by dynamin-related GTPases mitofusin (Mfn) 1/2 and optic atrophy type 1 (OPA1) promoting the OMM and inner mitochondrial membrane (IMM) fusion respectively. This process allows the function of an anomalous mitochondrion to be enhanced and averaged through combination with a healthy mitochondrion. (C) The stressed mitochondria also communicate with the nucleus through the mitochondrial unfolded protein response (UPRmt) and activate ATF4/5 and JNK/CHOP signaling pathways to induce the transcription of nuclear genes associated with mitochondrial survival and quality control. (D) Alternatively, impaired mitochondria may also be eliminated by mitophagy, triggered by the direct association of BNIP3 or FUNDC1 with LC3 or by marking mitochondria through the parkin-mediated polyubiquitination of OMM proteins. (E) Nuclear encoded mitochondrial proteins and mtDNA transcription are induced by PGC-1α that enhance mitochondrial biogenesis and maintain the mitochondrial mass. (F) ER–mitochondria communication through mitochondria-associated membranes (MAMs) allow molecules to be exchanged between these organelles and regulate the mitochondrial metabolism, bioenergetics, and signaling processes. MAMs are composed of ER proteins like PACS-2, Calnexin, and Mfn-2 and by mitochondrial proteins like VDAC, Mfn-2, and FUNDC1 among others.

Figure 2.

Mitochondrial retrograde signaling. (A) Mitochondria can be considered as an integration node. This organelle receives signals from the cytoplasm (Input), integrates the information, and generates responses (output). This response may regulate several cellular functions, generating a negative feedback on the input. (B) Cytoplasmic signals induce morphological and functional changes in mitochondria that regulate several intracellular functions such as signaling (eg, mROS generation), bioenergetics (ATP synthesis), and biosynthetic (eg, acetyl-CoA) roles. These roles are necessary for the whole cell function. (C) There are 2 mechanisms by which mitochondria regulate whole cell function: (1) by contact (eg, ER–mitochondria interaction), and (2) by distance (eg, mROS activate transcription factors to modulate nuclear gene expression). Communication by distance would include several molecules, such as small metabolites, peptides, and ions. These molecules would regulate nuclear gene expression, vesicle trafficking, and cell death, among others.

Figure 3.

Caloric restriction and exercise restore mitochondrial dysfunction. NCDs induce an alteration of functional and structural features of mitochondria. The energetic stress challenge induced by caloric restriction and exercise create a negative balance by altering the AMP/ATP and NAD+/NADH ratios. These changes are sensed by 2 main proteins, AMPK and SIRT1, that are able to phosphorylate and deacetylate correspondingly the mitochondrial biogenesis regulator PGC-1α. Alteration of energy homeostasis increases mitophagy, changes mitochondrial morphology (more elongated) allowing mROS production to be reduced, antioxidant capacity to be increased, and, on a differential manner, oxygen consumption rate (OCR) to be altered to ensure more efficient ATP to be maintained during caloric restriction or ATP synthesis for muscular work. These ATP-driven differences are allowed by more coupled electron transport chain assembly induced by changes in mitochondrial mass and a fused pattern encouraged by initial energetic sensors.