The fountain of youth of mitochondrial research: Research is targeting mitochondrial dysfunction to tackle aging and much more, but hype is an increasing concern

Abstract

A new wave of studies is untangling the connection between primary genetic mitochondrial diseases and the role of mitochondria in aging: what are the implications for longevity?

Figure 1. Mitochondria run parallel in mature cardiomyocytes

Adult mouse primary cardiomyocytes stained with TMRE (mitochondria, orange) and NucBlue (nuclei, blue). Winner of the Best Mitochondria Image 2022 award of the World Mitochondria Society (https://wms‐site.com/alert‐on‐mitochondria/1121‐winner‐of‐the‐best‐mitochondria‐image‐2022‐erminia‐donnarumma‐institut‐pasteur). Credit: Erminia Donnarumma, T. Wai’s Lab, Institut Pasteur, France. Reproduced with permission.

Figure 2. Pleiotropic effects of mitochondria in aging

Mitochondrial alterations in aging initiate with a decline in mitochondria stress‐response (MSR) pathways leading to the accumulation of mtDNA mutations, release of damaged toxic mitochondrial material (for example, intracellular molecules from senescent or dying cells, termed damage‐associated molecular patterns or DAMPs), generation of mitochondrial ROS, proteotoxicity, and deregulated metabolites (TCA intermediates, NAD⁺). These alterations have a broad detrimental effect on cellular homeostasis and, through a complex signaling mechanism (involving mitokines, metabolites, and more), contribute to systemic organismal decline and the onset of several age‐related diseases. Pharmacological modulation of the MSR, such as through the use of NAD⁺ enhancers or mitophagy inducers, can be effective strategies to prevent aging‐related cellular and organismal decline. In the figure, IR injury stands for ischemia‐reperfusion injury; NFLD for nonalcoholic fatty liver disease; and NASH for nonalcoholic steatohepatitis. Reproduced from Lima et al (2022) with permission.

Figure 3. Proposed mechanism for activators of VDAC1 promoter leading to VDAC1 overexpression, oligomerization, and activation of apoptosis and/or inflammation

(A) Apoptosis stimuli, stress, and pathological conditions activating VDAC1 promoter via transcription factors and Ca²⁺, thereby, inducing VDAC1 transcription, which leads to enhanced VDAC1 expression. (B) Overexpressed VDAC1 shifts the equilibrium to the VDAC1 oligomeric state with a large channel, mediating the release of apoptogenic proteins, leading to apoptosis and/or to the release of mtDNA or/and oxidized mtDNA fragments (fr‐mtDNA) leading to inflammation. VDAC1‐interacting molecules such as DIDS, VBIT‐4 and VBIT‐12, inhibit VDAC1 oligomerization and, thereby, the formation of the large channel and release of pro‐apoptotic proteins, subsequently, inhibiting apoptosis. (C) Summary of sequence of events induced by apoptosis stimuli, stress, and disease conditions leading to apoptosis and/or inflammation. Modified from Shoshan‐Barmatz et al (2020) with permission.

Figure B1. Principles of mitochondrial transfer

A prospective mother carrying a pathogenic mitochondrial DNA mutation can be offered mitochondrial transfer to reduce the risk of having a child affected by mitochondrial DNA disease. Two approaches have been used: pronuclear transfer (Panel A) and spindle transfer (Panel B), which allow the nuclear genome to be transferred to a donor zygote or oocyte containing mitochondria without the mitochondrial DNA mutation. A similar approach has been offered to women with infertility in the hope of improving their chances of having a child through mitochondrial transfer to unfertilized oocytes. Early work in this field involved the transfer of cytoplasm from a healthy young donor to oocytes that had been obtained from a prospective mother with age‐related infertility. More recently, spindle transfer has been used to transfer the nuclear DNA from an older mother's oocyte to an enucleated donor oocyte before in vitro fertilization (Panel C). Modified from Chinnery (2020) with permission.

Figure 4. Clinical features of Leigh syndrome (LS)

The most prevalent clinical features affect the brain, muscles, and eyes. Other clinical findings include dysfunctions in the cardiovascular, gastrointestinal, renal, auditory, and hematological systems. LS can present as early onset or late‐onset with abnormalities in at least three of the organ systems highlighted. LS results from pathogenic mutations in either the nuclear DNA or mitochondrial DNA that cause abnormalities in the OXPHOS capacities of the mitochondria. Hence, biochemical findings reflect these defects. Reproduced from Bakare et al (2021) with permission.