Metabolic features and regulation of the healing cycle-A new model for chronic disease pathogenesis and treatment

Mitochondrion. 2019 May;46:278-297. doi: 10.1016/j.mito.2018.08.001. Epub 2018 Aug 9.


Without healing, multicellular life on Earth would not exist. Without healing, one injury predisposes to another, leading to disability, chronic disease, accelerated aging, and death. Over 60% of adults and 30% of children and teens in the United States now live with a chronic illness. Advances in mass spectrometry and metabolomics have given scientists a new lens for studying health and disease. This study defines the healing cycle in metabolic terms and reframes the pathophysiology of chronic illness as the result of metabolic signaling abnormalities that block healing and cause the normal stages of the cell danger response (CDR) to persist abnormally. Once an injury occurs, active progress through the stages of healing is driven by sequential changes in cellular bioenergetics and the disposition of oxygen and carbon skeletons used for fuel, signaling, defense, repair, and recovery. >100 chronic illnesses can be organized into three persistent stages of the CDR. One hundred and two targetable chemosensory G-protein coupled and ionotropic receptors are presented that regulate the CDR and healing. Metabokines are signaling molecules derived from metabolism that regulate these receptors. Reframing the pathogenesis of chronic illness in this way, as a systems problem that maintains disease, rather than focusing on remote trigger(s) that caused the initial injury, permits new research to focus on novel signaling therapies to unblock the healing cycle, and restore health when other approaches have failed.

Keywords: Allostasis; Allostatic load; Antipurinergic therapy; Cell danger response; Ecoalleles; Ecogenetics; Healing cycle; Integrated stress response; M0, M1 and M2 mitochondria; Metabokines; Metabolic addiction; Metabolic memory; Mitochondrial nexus; Purinergic signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chronic Disease*
  • Energy Metabolism*
  • Gene Regulatory Networks*
  • Humans
  • Mass Spectrometry
  • Metabolome*
  • Metabolomics
  • Signal Transduction
  • Wound Healing / physiology*