Bioenergetic medicine

Abstract

Here we discuss a specific therapeutic strategy we call 'bioenergetic medicine'. Bioenergetic medicine refers to the manipulation of bioenergetic fluxes to positively affect health. Bioenergetic medicine approaches rely heavily on the law of mass action, and impact systems that monitor and respond to the manipulated flux. Since classically defined energy metabolism pathways intersect and intertwine, targeting one flux also tends to change other fluxes, which complicates treatment design. Such indirect effects, fortunately, are to some extent predictable, and from a therapeutic perspective may also be desirable. Bioenergetic medicine-based interventions already exist for some diseases, and because bioenergetic medicine interventions are presently feasible, new approaches to treat certain conditions, including some neurodegenerative conditions and cancers, are beginning to transition from the laboratory to the clinic. LINKED ARTICLES AbbreviationsAChEI, acetylcholine esterase inhibitor; AD, Alzheimer's disease; AMPK, AMP kinase; CoQ, coenzyme Q; COX, cytochrome oxidase; cybrid, cytoplasmic hybrid; DM, diabetes mellitus; ER, endoplasmic reticulum; ETC, electron transport chain; FA, Friedreich's ataxia; FAD, flavin adenine dinucleotide; FDG PET, fluorodeoxyglucose PET; HD, Huntington's disease; IP3, inositol triphosphate; MCI, mild cognitive impairment; MCT, monocarboxylate transporter; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; NAA, n-acetyl aspartate; OAA, oxaloacetate; PD, Parkinson's disease; PDHC, pyruvate dehydrogenase complex; PDK4, pyruvate dehydrogenase kinase 4; PGC1, peroxisome proliferator-activated receptor γ-complex 1; SERCA, sarcoendoplasmic reticulum calcium ATPase Bioenergetics refers to the chemistry and molecular physiology of energy metabolism. It is most often considered at the individual cell level, with a cell's bioenergetic status typically summarized as the amount of energy-yielding intermediates, such as ATP, it contains. The balance between a cell's rate of energy intermediate production and consumption determine this parameter.Multiple biochemical pathways contribute to a cell's bioenergetic state. Within cells, these pathways are variably compartmentalized or span compartments, and bioenergetic pathways are ultimately characterized by the passage of carbon that starts as part of one molecule and ends as another. Bioenergetic pathways, therefore, are characterized by movement through the pathway, or as a 'flux'.Bioenergetic changes occur in many diseases, including the mitochondrial encephalomyopathies, neurodegenerative diseases and cancer (Swerdlow, 2009b;Vander Heiden et al., 2009;Chaturvedi and Beal, 2013). In some disorders, bioenergetic perturbations are etiologically relevant. In others, bioenergetic changes induced by upstream pathologies mediate or amplify a particular phenotype or pathology. Mitochondrial dysfunction is frequently seen, and diseases in which mitochondria appear to play particularly upstream roles are sometimes considered 'mitochondriopathies...

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…The integrity and viability of the bioenergetic system is a fundamental determinant of synaptic and brain function [9,[30][31][32]. Although the human brain accounts for 2 % of the body's mass, it consumes 20 % of the body's fuel supply for Fig.…”

“…Glycolysis, the citric acid cycle, and mitochondrial oxidative phosphorylation are then coordinated to generate ATP [31,32]. Compromised glucose uptake and metabolism provide a therapeutic target for AD prevention and intervention.…”

“…A decline in mitochondrial function can occur decades prior to clinical diagnosis of AD and thus may serve as a biomarker of AD risk, as well as a therapeutic target [12,24,32,67]. Preclinical in vitro and in vivo AD models have demonstrated a decline in mitochondrial function, including reduced mitochondrial respiration, decreased metabolic enzyme expression and activity, increased oxidative stress, and increased mitochondrial Aβ load and ABAD expression, prior to AD pathology [12,13,15,24,34,38].…”

“…Coenzyme Q (CoQ) and its synthetic watersoluble analogue, idebenone, have been proposed for AD treatment [32,68,83]. CoQ is imbedded in the mitochondrial inner membrane and transports electrons from complex I/II to complex III in the ETC.…”

“…In addition, CoQ can function as a ROS scavenger [68]. While CoQ supplementation has benefit in persons with CoQ synthesis disorders and in preclinical mouse models of AD, it is ineffective as a therapeutic in persons with AD [32,65,83]. In a randomized, double-blind, multicenter study with 450 participants with mild-to-moderate AD, Idebenone showed minimal cognitive benefit [69][70][71], but was not approved for treatment of AD based on results not reaching statistical significance in larger trials [70][71][72].…”