An evolutionary, or “Mitocentric” perspective on cellular function and disease

Brown, Jamelle; Sammy, Melissa J; Ballinger, Scott W.

doi:10.1016/j.redox.2020.101568

Cited by 22 publications

(19 citation statements)

References 251 publications

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“…Mitochondria are astounding cytoplasmic organelles with a monophyletic origin from a α-proteobacterial ancestor, which genes were lost or transferred to the eukaryotic (nuclear) genome over millions of years. As consequence, the modern mitochondrial genome resides in two compartments, the mitochondrion (mtDNA) and the nucleus (nDNA), comprising thousands of copies of genes [76]. The mtDNA is replicated independently of the host genome and in humans encodes 13 proteins that are core constituents of OXPHOS.…”

Section: Mitochondria Are Hubs In Metabolismmentioning

confidence: 99%

Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

2020

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Cancer cells reprogram their metabolism to meet bioenergetics and biosynthetic demands. The first observation of metabolic reprogramming in cancer cells was made a century ago (“Warburg effect” or aerobic glycolysis), leading to the classical view that cancer metabolism relies on a glycolytic phenotype. There is now accumulating evidence that most cancers also rely on mitochondria to satisfy their metabolic needs. Indeed, the current view of cancer metabolism places mitochondria as key actors in all facets of cancer progression. Importantly, mitochondrial metabolism has become a very promising target in cancer therapy, including for refractory cancers such as Pancreatic Ductal AdenoCarcinoma (PDAC). In particular, mitochondrial oxidative phosphorylation (OXPHOS) is an important target in cancer therapy. Other therapeutic strategies include the targeting of glutamine and fatty acids metabolism, as well as the inhibition of the TriCarboxylic Acid (TCA) cycle intermediates. A better knowledge of how pancreatic cancer cells regulate mitochondrial metabolism will allow the identification of metabolic vulnerabilities and thus novel and more efficient therapeutic options for the benefit of each patient.

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Section: Mitochondria Are Hubs In Metabolismmentioning

confidence: 99%

Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

2020

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“…It can be hypothesized that UCP2 works to reduce ROS produced in population with warm climates to counteract the damage of ROS production. In fact, it has been described that different nuclear–mtDNA combinations influence organelle oxidant production in a population-specific way ( Brown et al, 2020 ). American individuals of African ancestry, whose ancestry is related to geographical areas characterized by hot climates, have a more “economical” mitochondrial transport that produces the same level of ATP having a lower oxygen consumption, but at the same time producing more DNA damage ( Krzywanski et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Investigating Mitonuclear Genetic Interactions Through Machine Learning: A Case Study on Cold Adaptation Genes in Human Populations From Different European Climate Regions

et al. 2020

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Cold climates represent one of the major environmental challenges that anatomically modern humans faced during their dispersal out of Africa. The related adaptive traits have been achieved by modulation of thermogenesis and thermoregulation processes where nuclear (nuc) and mitochondrial (mt) genes play a major role. In human populations, mitonuclear genetic interactions are the result of both the peculiar genetic history of each human group and the different environments they have long occupied. This study aims to investigate mitonuclear genetic interactions by considering all the mitochondrial genes and 28 nuclear genes involved in brown adipose tissue metabolism, which have been previously hypothesized to be crucial for cold adaptation. For this purpose, we focused on three human populations (i.e., Finnish, British, and Central Italian people) of European ancestry from different biogeographical and climatic areas, and we used a machine learning approach to identify relevant nucDNA–mtDNA interactions that characterized each population. The obtained results are twofold: (i) at the methodological level, we demonstrated that a machine learning approach is able to detect patterns of genetic structure among human groups from different latitudes both at single genes and by considering combinations of mtDNA and nucDNA loci; (ii) at the biological level, the analysis identified population-specific nuclear genes and variants that likely play a relevant biological role in association with a mitochondrial gene (such as the “obesity gene” FTO in Finnish people). Further studies are needed to fully elucidate the evolutionary dynamics (e.g., migration, admixture, and/or local adaptation) that shaped these nucDNA–mtDNA interactions and their functional role.

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“…Since NETs represented the target parameter of the primary study, these conditions might have biased the study results, and were therefore matched in the control and septic shock group. Since these conditions are also connected to an impaired mitochondrial function, the matching strategy is also appropriate for this secondary analysis [ 21 , 22 , 23 , 24 ]. Visceral surgical patients underwent major abdominal surgery (MAS), such as Whipple’s procedure, oncological gastric or esophageal resection, or colectomy, whereas all cardiac surgical patients received coronary artery bypass graft (CABG) surgery.…”

Section: Methodsmentioning

confidence: 99%

Blood Levels of Free-Circulating Mitochondrial DNA in Septic Shock and Postsurgical Systemic Inflammation and Its Influence on Coagulation: A Secondary Analysis of a Prospective Observational Study

Schneck

Edinger

Hecker

et al. 2020

JCM

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Major surgery is regularly associated with clinical signs of systemic inflammation, which potentially affects the rapid identification of sepsis. Therefore, this secondary analysis of an observational study aims to determine whether NADH dehydrogenase 1 (ND1) mitochondrial DNA (mtDNA) could be used as a potential biomarker for the discrimination between septic shock and postsurgical systemic inflammation. Overall, 80 patients were included (septic shock (n = 20), cardiac artery bypass grafting (CABG, n = 20), major abdominal surgery (MAS, n = 20), and matched controls (CTRL, n = 20)). Quantitative PCR was performed to measure ND1 mtDNA. Thromboelastography was used to analyze the coagulatory system. Free-circulating ND1 mtDNA levels were significantly higher in septic shock patients compared to patients suffering from post-surgical inflammation ({copies/µL}: CTRL: 1208 (668–2685); septic shock: 3823 (2170–7318); CABG: 1272 (417–2720); and MAS: 1356 (694–2845); CTRL vs. septic shock: p < 0.001; septic shock vs. CABG: p < 0.001; septic shock vs. MAS: p = 0.006; CABG vs. MAS: p = 0.01). ND1 mtDNA levels in CABG patients showed a strong positive correlation with fibrinogen (correlation coefficient [r]= 0.57, p < 0.001) and fibrinogen-dependent thromboelastographic assays (maximum clot firmness, EXTEM: r = 0.35, p = 0.01; INTEM: r = 0.31, p = 0.02; FIBTEM: r = 0.46, p < 0.001). In conclusion, plasma levels of free-circulating ND1 mtDNA were increased in septic shock patients and were discriminative between sepsis and surgery-induced inflammation. Furthermore, this study showed an association between ND1 mtDNA and a fibrinogen-dependent pro-coagulatory shift in cardiac surgical patients.

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An evolutionary, or “Mitocentric” perspective on cellular function and disease

Cited by 22 publications

References 251 publications

Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

Investigating Mitonuclear Genetic Interactions Through Machine Learning: A Case Study on Cold Adaptation Genes in Human Populations From Different European Climate Regions

Blood Levels of Free-Circulating Mitochondrial DNA in Septic Shock and Postsurgical Systemic Inflammation and Its Influence on Coagulation: A Secondary Analysis of a Prospective Observational Study

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