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Review
. 2021 Feb 22:9:625020.
doi: 10.3389/fcell.2021.625020. eCollection 2021.

mtDNA Heteroplasmy at the Core of Aging-Associated Heart Failure. An Integrative View of OXPHOS and Mitochondrial Life Cycle in Cardiac Mitochondrial Physiology

Alvaro A Elorza  1   2 , Juan Pablo Soffia  1   2
Affiliations
Review

mtDNA Heteroplasmy at the Core of Aging-Associated Heart Failure. An Integrative View of OXPHOS and Mitochondrial Life Cycle in Cardiac Mitochondrial Physiology

Alvaro A Elorza et al. Front Cell Dev Biol. .

Abstract

The most common aging-associated diseases are cardiovascular diseases which affect 40% of elderly people. Elderly people are prone to suffer aging-associated diseases which are not only related to health and medical cost but also to labor, household productivity and mortality cost. Aging is becoming a world problem and it is estimated that 21.8% of global population will be older than 65 years old in 2050; and for the first time in human history, there will be more elderly people than children. It is well accepted that the origin of aging-associated cardiovascular diseases is mitochondrial dysfunction. Mitochondria have their own genome (mtDNA) that is circular, double-stranded, and 16,569 bp long in humans. There are between 500 to 6000 mtDNA copies per cell which are tissue-specific. As a by-product of ATP production, reactive oxygen species (ROS) are generated which damage proteins, lipids, and mtDNA. ROS-mutated mtDNA co-existing with wild type mtDNA is called mtDNA heteroplasmy. The progressive increase in mtDNA heteroplasmy causes progressive mitochondrial dysfunction leading to a loss in their bioenergetic capacity, disruption in the balance of mitochondrial fusion and fission events (mitochondrial dynamics, MtDy) and decreased mitophagy. This failure in mitochondrial physiology leads to the accumulation of depolarized and ROS-generating mitochondria. Thus, besides attenuated ATP production, dysfunctional mitochondria interfere with proper cellular metabolism and signaling pathways in cardiac cells, contributing to the development of aging-associated cardiovascular diseases. In this context, there is a growing interest to enhance mitochondrial function by decreasing mtDNA heteroplasmy. Reduction in mtDNA heteroplasmy is associated with increased mitophagy, proper MtDy balance and mitochondrial biogenesis; and those processes can delay the onset or progression of cardiovascular diseases. This has led to the development of mitochondrial therapies based on the application of nutritional, pharmacological and genetic treatments. Those seeking to have a positive impact on mtDNA integrity, mitochondrial biogenesis, dynamics and mitophagy in old and sick hearts. This review covers the current knowledge of mitochondrial physiopathology in aging, how disruption of OXPHOS or mitochondrial life cycle alter mtDNA and cardiac cell function; and novel mitochondrial therapies to protect and rescue our heart from cardiovascular diseases.

Keywords: OXPHOS; ROS; aging; biogenesis; cardiac; heart failure; mitophagy; mtDNA heteroplasmy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Keeping a healthy mitochondrial population. Mitochondria’s health depends on two complementary systems. The first system is the OXPHOS. This will provide energy (ATP) and reactive oxygen species (ROS) which are both necessary to drive the second system: The Mitochondrial Life cycle. Through mitochondrial fusion and fission events (Mitochondrial dynamics, MtDy), mitochondria are segregated to be eliminated by mitophagy. The induction of mitophagy is coupled with mitochondrial biogenesis which involves mitochondrial DNA (mtDNA) replication. mtDNA encodes for 11 respiratory complex subunits (7 subunits for complex I, 1 for complex III, 3 for complex IV) plus 2 subunits of the ATP synthase that will allow OXPHOS assembly to keep going the virtuous circle. Any disruption or delay in this running circle will end up in the loss of energy, mutations in mtDNA, decrease in mtDNA copy number and increased ROS leading to mitochondrial dysfunction, cell death, aging and aging-associated diseases.
FIGURE 2
FIGURE 2
Proposed Model of Cardiac Aging. The core of our model and the main driver of aging is mtDNA heteroplasmy. In aging, two vicious cycles were defined. Vicious cycle No1 will progressively increase the level of mtDNA heteroplasmy and decrease OXPHOS efficiency at the point to affect mitophagy and set the onset of Vicious cycle No2 that will progressively inhibit mitochondrial biogenesis and antioxidant response due to inhibition of PGC-1α and stimulation and upregulation of NCoR1. As a result, dysfunctional mitochondria will accumulate, increasing the number of mitoflashes and pathological ROS to finally trigger the mPTP opening and the release of DAMPs to initiate an inflammatory cell response and an apoptotic/necrotic stimulus. Furthermore, a metabolic switch from fatty acid oxidation to glucose oxidation will occur. Altogether, these events lead to cardiovascular diseases and cardiac failure. On the other hand, in young people, a low level of mtDNA heteroplasmy will keep the efficiency of the OXPHOS system which will maintain low NAD + /NADH and AMP/ATP ratios and a physiological amount of ROS. These conditions allow the Virtuous Cycle where MtDy will segregate dysfunctional mitochondrial units for degradation by mitophagy and will activate PGC-1α and NFE2L2 for mitochondrial biogenesis. Of note, cardiac cells are able to expel out mitochondria in vesicles called exospheres that are degraded by surrounding macrophages. In this model, we hypothesized that exosphere release, which is dependent on the autophagic machinery, is decreased in aging. Also, it is not clear yet whether in cardiac aging the protein MUL1 is involved in mitophagy, but it has been shown to be upregulated under cardiac damage. Along with NCoR1, another transcriptional corepressor like SMRT has been shown to be involved in aging.
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