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Naviaux, R. K. (2023). Mitochondrial and metabolic features of salugenesis and the healing cycle. Mitochondrion, 70, 131–163. Added by: Dr. Enrique Feoli (19/06/2025, 20:41) Last edited by: Dr. Enrique Feoli (20/06/2025, 17:29) |
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| Resource type: Journal Article DOI: 10.1016/j.mito.2023.04.003 ID no. (ISBN etc.): 1567-7249 BibTeX citation key: Naviaux2023 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Healing cycle Keywords: Aging, Allostatic load, Anthropocene, Cell danger response, Chronic disease, Ecoalleles, Healing cycle, Integrated stress response, Metabolic memory, Metabolic reprogramming, Mitochondria, Mitotypes, Phenomics, Pluricausal disease, Polyvagal theory, Pónos, Purinergic signaling, Purinosis, Salugenesis, Synthetic phenotypes Creators: Naviaux Collection: Mitochondrion |
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| Abstract |
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Pathogenesis and salugenesis are the first and second stages of the two-stage problem of disease production and health recovery. Salugenesis is the automatic, evolutionarily conserved, ontogenetic sequence of molecular, cellular, organ system, and behavioral changes that is used by living systems to heal. It is a whole-body process that begins with mitochondria and the cell. The stages of salugenesis define a circle that is energy- and resource-consuming, genetically programmed, and environmentally responsive. Energy and metabolic resources are provided by mitochondrial and metabolic transformations that drive the cell danger response (CDR) and create the three phases of the healing cycle: Phase 1—Inflammation, Phase 2—Proliferation, and Phase 3—Differentiation. Each phase requires a different mitochondrial phenotype. Without different mitochondria there can be no healing. The rise and fall of extracellular ATP (eATP) signaling is a key driver of the mitochondrial and metabolic reprogramming required to progress through the healing cycle. Sphingolipid and cholesterol-enriched membrane lipid rafts act as rheostats for tuning cellular sensitivity to purinergic signaling. Abnormal persistence of any phase of the CDR inhibits the healing cycle, creates dysfunctional cellular mosaics, causes the symptoms of chronic disease, and accelerates the process of aging. New research reframes the rising tide of chronic disease around the world as a systems problem caused by the combined action of pathogenic triggers and anthropogenic factors that interfere with the mitochondrial functions needed for healing. Once chronic pain, disability, or disease is established, salugenesis-based therapies will start where pathogenesis-based therapies end.
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| Notes |
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The careful regulation of the cellular fates for each of the major atoms extracted from the chemosphere and utilized by living systems in the biosphere is critical for survival. This means that the regulation of oxygen (O), carbon (C), nitrogen (N), sulfur (S), phosphorus (P), sodium (Na), potassium (K), calcium (Ca), chloride (Cl), magnesium (Mg), iron (Fe), and 30 other trace elements in regulated proportion, is critical for survival. The stoichiometry of these elements, classically a 106:16:1 ratio of carbon to nitrogen to phosphorus (C:N:P), was first studied by Alfred Redfield in ocean plankton and thought to be a fixed biological property of life (Redfield, 1934). Today it is known that short-term changes elemental ratios in cells are determined by the chemical balance between oxidation and reduction, which is determined in large part by the dissolved oxygen concentration in the surrounding water. At ocean scales, the oxygen content of water is decreased by things like agricultural runoff and fertilizer. These pollutants create dead zones caused by hypoxia (Diaz and Rosenberg, 2008). Hypoxia triggers a cellular stress response that changes metabolism and changes the C:N:P ratio in cells (Quan and Falkowski, 2009). Hypoxia can be caused by decreased oxygen delivery, increased oxygen consumption, or both. Because mitochondria operate as the biochemical sinks for oxygen consumption, small changes in oxygen consumption by mitochondria lead to rapid changes in the dissolved oxygen content in the cytoplasm of cells. When mitochondrial oxygen consumption decreases and the delivery of oxygen to the cell by surrounding capillaries is unchanged, the dissolved oxygen concentration in the cytoplasm rises like water in a bowl. When mitochondria use less oxygen for basal energy metabolism, the remaining excess of cytoplasmic oxygen is used for ROS production and oxidative shielding to protect the cell from many different kinds of physical, chemical, and microbial danger (Naviaux, 2012).
In a model of acute cell danger signaling, systemic injection of extracellular ATP was found to reprogram over 30 different biochemical pathways, and caused changes in body temperature, basal metabolic rate, and behavior in mice. The top 15 pathways that were changed by ATP-associated purinergic signaling included phospholipids, sphingolipids, microbiome, purines, methylation and 1-carbon metabolism, fatty acid oxidation, eicosanoids, glycolysis, bile acids, pyrimidines, the Krebs cycle, transsulfuration and glutathione, polyamines, and the urea cycle. ATP injection also unmasked a latent metabolic memory response in a mouse model of autism. ADP, AMP, cAMP, and adenosine injection produced similar but non-identical effects. In contrast, systemic injection of GTP, cGMP, UTP, TTP, or CTP had no significant effect. Males were found to be more sensitive to the behavioral effects of eATP. Females were more sensitive to the metabolic effects (Zolkipli-Cunningham et al., 2021).
19.1. Purinergic regulation of ROS and redox biologyAll stressors trigger a mismatch between four factors: 1) the rate of fuel supply (electrons and protons), and atomic building blocks (carbon, oxygen, nitrogen, sulfur, phosphorus, etc.), 2) the rate of energy demand (cellular ATP turnover), 3) the rate of cellular metabolic waste and toxin removal (set by vascular and cell membrane permeability factors), and 4) the maximum work capacity (set jointly by the rate of oxygen delivery and the mitochondrial capacity to convert dissolved O2 to H2O and ATP). Any mismatch in these factors results in an increase in intracellular reactive oxygen species (ROS), which inhibits mitochondrial network fusion and the ability to fully metabolize eATP to adenosine. Purinergic signaling through P2X, P2Y, and P1 receptors exerts powerful control over redox biology. While eATP and eADP promote the production of ROS and reactive nitrogen species (RNS), their metabolic end products eAMP and extracellular adenosine (eAdo) downregulate ROS and RNS production (Savio et al., 2021). Sequential metabolic transformations of ATP to adenosine are used to extinguish cell danger signals and to prepare for the return of safety and housekeeping functions. Because of this pivotal importance for the regulation of danger and safety signals, eATP and adenosine have been called the primordial signaling molecules (Rho and Boison, 2022). Persistence of any phase of the CDR leads to incomplete healing and symptoms of chronic disease, pain, and disability. The restoration of the natural periodicities—the circadian and seasonal rhythms—of the health cycle (Fig. 4A) helps to actively extinguish the metabolic memories caused by CDR persistence associated with chronic illness (Fig. 4B
20.4. Purinosis and its comorbiditiesAcute inflammation is known by its signs: tumor (swelling), dolor (pain), rubor (redness), calor (heat), and functio laesa (dysfunction). Emerging evidence suggests that the symptoms of inflammation and pain are downstream effects of the most fundamental threat to the life of a cell—the loss of the store of energy that drives the engines of life, the loss of intracellular pools of ATP (iATP), and subsequent eATP-related purinergic signaling (Inoue, 2022). Loss of iATP from a cell is like the loss of blood in an animal. If the loss cannot be stopped, the cell and the animal perish. The life-or-death stakes have led to the evolution of powerful gene sets and countermeasures to stop these archetypal threats to life. Hemorrhage is the term used to describe life-threatening blood loss. There is not yet a term to describe the life-threatening ATP loss from the cell. The term purinosis is proposed to describe the loss of iATP pools (ATP chemical pressure) in the cell, stress- and redox-gated ATP efflux, and the associated increase in purinergic and metabokine signaling to neighboring cells by eATP, related nucleotides, and metabolites.
The salugenesis model posits that purinosis is the proximate cause of acute inflammation, chronic pain, and their behavioral comorbidities. One cause of purinosis is a non-physiologic drop in, or inhibition of, mitochondrial oxygen consumption. This is associated with an increase in ROS and RNS. In the absence of a decreased blood supply, decreased mitochondrial oxygen, hydrogen, and electron consumption lead to a decrease in mitochondrial water (H2O) production by cytochrome c oxidase, and to an increase the dissolved oxygen content of the cell. Oxygen is lipophilic and the excess diatomic oxygen (O2) is absorbed into organellar and cellular membranes, driving the production of superoxide (O2–), hydrogen peroxide (H2O2), nitric oxide (NO.), peroxynitrite (ONOO–), and reactive aldehydes for purposes of oxidative shielding and defense against microbial attack and many other kinds of threat.
By placing mitochondrial oxygen consumption at the hub of all the cell threat detection systems, even biophysical threats like hypertension that inhibit mitochondrial oxygen consumption will trigger an increase in dissolved oxygen and a cascade of downstream effects (Ryanto et al., 2023). Once a threat is detected, expression of inflammatory proteins like the mitochondrial cholesterol transporter known as the 18 kDa translocator protein (TSPO, formerly known as PBR, the peripheral benzodiazepine receptor) is increased (El Chemali et al., 2022). Cellular cholesterol is biophysically concentrated in oxygen-enriched phospholipid membranes. This permits mitochondrial and cell membranes to buffer the excess oxygen by absorbing it from the cytoplasm (Al-Samir et al., 2021). Sphingolipids are recruited to the cholesterol-enriched membrane lipid rafts and sensitize cells to purinergic and cytokine signaling. Further membrane oxygen accumulation leads to carbonylation and cross-linking of membrane proteins, lipid peroxidation, membrane stiffening, and changes in cell membrane potential that activate voltage-gated calcium influx (Klug et al., 2023), membrane lipid glutathione peroxidases, lipoxygenases, and phospholipase A2 (PLA2) (Hermann et al., 2014). Time-resolved fluorescence anisotropy experiments show that changes in membrane fluidity occur very rapidly, within 0.15 ms of a change in the partial pressure of oxygen (pO2) or temperature (Dumas et al., 1997). Excess oxygen dissolved in the cytosolic and nuclear compartments is converted to H2O2 by the polyamine oxidase, spermine oxidase (SMOX) (Diaz et al., 2022), which simultaneously produces highly reactive aldehydes like 3-aminopropanal and acrolein (Murray Stewart et al., 2018). If counter-regulatory mechanisms are unable to repair the damage, the cell is removed by ferroptosis (Xie et al., 2022), apoptosis, or by other active cell death pathways. This makes good sense from an evolutionary perspective. The most damaged cells are likely to contain the largest pools of invading viruses, bacteria, fungi, or parasites, or contain the highest exposure to uncaged metals and to toxins that could endanger neighboring cells. By removing the most damaged cells and sounding the alarm, neighboring cells are protected. One of the earliest signs of the abnormal rise in dissolved oxygen concentration is the opening of redox-gated PANX1 channels in the cell membrane to release ATP and signal danger (Retamal, 2014). Supporting the key importance of ATP release in chronic pain and neuroinflammation is the finding that PANX1 channel inhibitors are potent inhibitors of both (Bravo et al., 2014, Seo et al., 2021).
Purinosis is distinct from the concept of hyperpurinergia. Hyperpurinergia can result from one or more of four processes: 1) cell damage or stress-related release of increased amounts of ATP from the cell resulting in decreased intracellular pools (purinosis sensu stricto), 2) excess production and subsequent release of purines from the cell as caused by certain genetic disorders of purine salvage, e.g., Lesch-Nyhan syndrome, and synthesis, e.g., phosphoribosyl pyrophosphate (PRPP) synthase superactivity, 3) increased levels of eATP associated with increased receptor activation and signaling, and 4) hypersensitivity to normal, decreased, or pulsed levels of eATP leading to amplified or brittle responses to purinergic signaling. The use of the word purinosis permits mechanistic studies of inflammation to be redirected and refocused on the proximate cause of the myriad downstream effects of inflammation. If the feedback circuits illustrated in Fig. 8 are correct, then at least three intervention points can be identified that will relieve chronic pain and result in improvements in its comorbidities. These interventions include: 1) removal of any remaining external triggers and sources of injury, 2) behavioral salugenesis therapies, and 3) drug and device salugenesis therapies. As with many salugenesis-directed therapies, these three interventions are expected to be synergistic.
21. Supertraits, healing, and longevityThe health and healing cycles are evolutionary supertraits that undergo selection like physical traits like fins and wings. Selection occurs by both predictable and unpredictable environmental factors in the context of life history exposures during each generation. The phenotype of successful healing relies upon the synergistic interaction of at least 7 elements or subsystems that must co-evolve as a supertrait. These subsystems include 1) purinergic (ATP-related) and ROS signaling, 2) mitochondrial metabolism and quality control by mitophagy, 3) the autonomic polyvagal parasympathetic (Porges, 2001) and sympathetic nervous systems, 4) the neuroendocrine and hypothalamic pituitary axis (HPA) systems, 5) cytokines, innate and adaptive immune systems, 6) the microbiome and enteric nervous system, and 7) the gene expression network known as the conserved transcriptional response to adversity (CTRA) (Cole, 2019). Primary disturbance of any one of the elements of the healing cycle will produce adaptive changes in the other 6 elements. None can be changed without changing the others. Not surprisingly, the functional elements of the healing cycle overlap with genetic subsystems that regulate longevity (Farre et al., 2021). Longevity is tightly calibrated to match changes in whole-body mitochondrial function. For example, mitochondrial bioenergetic function measured as the basal metabolic rate (BMR) in calories and calculated from the basal rate of oxygen consumption (V̇ O2) is a predictor of longevity and mortality. Hypermetabolism is costly. Even a 10 % increase in BMR above age-matched healthy control levels leads to increased mortality (Ruggiero et al., 2008). Reciprocally, many different hypometabolic states have evolved like hibernation and dauer, to provide protection during times of life-threatening environmental stress or illness (Gorr, 2017).
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |