Functional Mitochondria in Health and Disease

Abstract

The ability to rapidly adapt cellular bioenergetic capabilities to meet rapidly changing environmental conditions is mandatory for normal cellular function and for cancer progression. Any loss of this adaptive response has the potential to compromise cellular function and render the cell more susceptible to external stressors such as oxidative stress, radiation, chemotherapeutic drugs, and hypoxia. Mitochondria play a vital role in bioenergetic and biosynthetic pathways and can rapidly adjust to meet the metabolic needs of the cell. Increased demand is met by mitochondrial biogenesis and fusion of individual mitochondria into dynamic networks, whereas a decrease in demand results in the removal of superfluous mitochondria through fission and mitophagy. Effective communication between nucleus and mitochondria (mito-nuclear cross talk), involving the generation of different mitochondrial stress signals as well as the nuclear stress response pathways to deal with these stressors, maintains bioenergetic homeostasis under most conditions. However, when mitochondrial DNA (mtDNA) mutations accumulate and mito-nuclear cross talk falters, mitochondria fail to deliver critical functional outputs. Mutations in mtDNA have been implicated in neuromuscular and neurodegenerative mitochondriopathies and complex diseases such as diabetes, cardiovascular diseases, gastrointestinal disorders, skin disorders, aging, and cancer. In some cases, drastic measures such as acquisition of new mitochondria from donor cells occurs to ensure cell survival. This review starts with a brief discussion of the evolutionary origin of mitochondria and summarizes how mutations in mtDNA lead to mitochondriopathies and other degenerative diseases. Mito-nuclear cross talk, including various stress signals generated by mitochondria and corresponding stress response pathways activated by the nucleus are summarized. We also introduce and discuss a small family of recently discovered hormone-like mitopeptides that modulate body metabolism. Under conditions of severe mitochondrial stress, mitochondria have been shown to traffic between cells, replacing mitochondria in cells with damaged and malfunctional mtDNA. Understanding the processes involved in cellular bioenergetics and metabolic adaptation has the potential to generate new knowledge that will lead to improved treatment of many of the metabolic, degenerative, and age-related inflammatory diseases that characterize modern societies.

Keywords: mito-nuclear cross talk; mitochondrial DNA; mitochondrial DNA mutations; mitochondrial stress signals; mitochondrial transfer; mitochondriopathies; mitopeptides.

Figure 1

Mitochondrial involvement in fundamental cellular pathways and processes.

Figure 2

Bioenergetic plasticity is central to the ability of cells to adapt to their ever-changing microenvironment. Mitochondrial and nuclear mutations in respiratory subunits, mitochondrial chaperones and proteases and other mitochondrial proteins can lead to compromised oxidative phosphorylation (OXPHOS). In response, damaged mitochondria send out mitostress signals such as increased reactive oxygen species (ROS) and exhibit decreased inner mitochondrial membrane potential. The latter causes a drop in mitochondrial ATP levels, increased mitochondrial and cytoplasmic NADH, and increased cytoplasmic calcium. In addition, mtDNA and nDNA mutations as well as increased ROS cause aggregation of damaged and misfolded proteins in the mitochondrial matrix, leading to prototoxic stress. Mitometabolites affect epigenetic modifications. The nucleus responds to these mitostress signals by activating one or more stress response pathways, depending on the type and duration of the stress signal. Repair of damaged DNA, dilution of faulty mtDNA copies by fusion and mitogenesis, removal of faulty mtDNA copies by fission followed by mitophagy, removal of protein aggregates by the mitochondrial unfolded protein response (mtUPR), removal of faulty mitochondria by the integrated stress response (ISR) and a shift from mitochondrial to glycolytic/lactate metabolism all ensure that the energy demands of cells are met. If OXPHOS cannot be restored, failing mitochondria are removed though mitophagy. In extreme cases, the cell undergoes apoptosis or replaces faulty mitochondria with functional mitochondria from other cells.

Figure 3

Mitochondrial quality control involves changes to the mitochondrial network to maintain bioenergetics homeostasis. Fusion (1) of additional mitochondria to the existing network occurs when the bioenergetics demands of the cell are not met. When damaged mitochondria cannot be repaired, they can be removed from the network through fission (2) followed by removal from the cell though mitophagy (3). Transfer of functional mitochondria from external sources through tunneling nanotubules (TNTS) (4), vesicles (5), or direct cytoplasmic fusion (6) can replenish a damaged or deficient mitochondrial network.

Figure 4

Stressors affect nuclear cross talk through changes in gene expression. Stressors such as oxidative stress, radiation, chemotherapeutic drugs, hypoxia, etc., cause genetic and epigenetic changes to both nDNA and mitochondrial DNA (mtDNA). The resulting changes in gene expression result in altered cellular bioenergetics, often leading to decreased oxidative phosphorylation. Mitochondrial stressors (a decrease in mitochondrial membrane potential, ATP levels, NADH levels, and increased mitopeptide expression, etc.) elicit nuclear stress responses. Stress pathway activation (mtDNA damage repair, mitochondrial biogenesis and fusion, switching to glycolytic metabolism, etc.) results in a return to bioenergetics homeostasis, restoring cellular function.