Natural and Artificial Mechanisms of Mitochondrial Genome Elimination

Zakirova, E. G.; Muzyka, V. V.; Мазунин, И. О.; Orishchenko, Кonstantin E.

doi:10.3390/life11020076

Cited by 4 publications

(3 citation statements)

References 212 publications

(272 reference statements)

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“…As hinted earlier, one of the most promising avenues of research resulting from this paper is the relationship between symbiosis and aging. An optimal control approach to explaining aging suggests that there exists a threshold at which it is optimal for the body to allow cell death instead of repairing damaged cells [ 23 ]. This threshold is in part determined by a repair cost dependent on the senescence of cells, which we now postulate to be the result of a signaling game.…”

Section: Discussionmentioning

confidence: 99%

How Mitochondrial Signaling Games May Shape and Stabilize the Nuclear-Mitochondrial Symbiosis

Casey,

Kumaran,

Massey

et al. 2024

Biology

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The eukaryotic lineage has enjoyed a long-term “stable” mutualism between nucleus and mitochondrion, since mitochondrial endosymbiosis began about 2 billion years ago. This mostly cooperative interaction has provided the basis for eukaryotic expansion and diversification, which has profoundly altered the forms of life on Earth. While we ignore the exact biochemical details of how the alpha-proteobacterial ancestor of mitochondria entered into endosymbiosis with a proto-eukaryote, in more general terms, we present a signaling games perspective of how the cooperative relationship became established, and has been maintained. While games are used to understand organismal evolution, information-asymmetric games at the molecular level promise novel insights into endosymbiosis. Using a previously devised biomolecular signaling games approach, we model a sender–receiver information asymmetric game, in which the informed mitochondrial sender signals and the uninformed nuclear receiver may take actions (involving for example apoptosis, senescence, regeneration and autophagy/mitophagy). The simulation shows that cellularization is a stabilizing mechanism for Pareto efficient sender/receiver strategic interaction. In stark contrast, the extracellular environment struggles to maintain efficient outcomes, as senders are indifferent to the effects of their signals upon the receiver. Our hypothesis has translational implications, such as in cellular therapy, as mitochondrial medicine matures. It also inspires speculative conjectures about how an analogous human–AI endosymbiosis may be engineered.

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Section: Discussionmentioning

confidence: 99%

How Mitochondrial Signaling Games May Shape and Stabilize the Nuclear-Mitochondrial Symbiosis

Casey,

Kumaran,

Massey

et al. 2024

Biology

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“…In vitro cytoplasmic hybrid (cybrid) cell system was the original mitochondrial delivery method in an AD model. Cybrids result from the fusion of mt-DNA depleted (rho0) cells with mitochondria from AD patient platelets [ 125 - 127 ]. Peptide- mediated allogeneic mitochondrial delivery (PMD) is a novel technique that facilitates the incorporation of mitochondria into Parkinson’s disease (PD) rat models.…”

Section: Possible Mitochondrially Targeted Interventions In Admentioning

confidence: 99%

Mitochondrially-Targeted Therapeutic Strategies for Alzheimer’s Disease

Onyango

Bennett

Stokin

2021

CAR

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: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments avail- able for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initi- ation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mito- chondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mito- chondrial systems biology. We review evidence for mitochondrial impairments ranging from mito- chondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expres- sion, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dy- namics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could poten- tially alter the course of this progressive, heterogeneous Disease while being cognizant that success- ful future therapeutics may require a combinatorial approach.

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“…Another important process whose dysregulation can lead to severe pathologies is the elimination of mitochondrial genome. Orishchenko and colleagues [ 9 ] review the mechanisms underlying the regulation of heteroplasmy level and mtDNA segregation, illustrating in detail the natural process of mitochondrial genome elimination in both the somatic cells and the germline. The development of methodologies for artificial manipulation of the mtDNA heteroplasmy level that aim either to prevent or potentially cure human diseases associated with mitochondrial dysfunction, is also examined.…”

mentioning

confidence: 99%