31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle.

Abstract

The bioenergetic capacity of skeletal muscle in a 17-year-old patient with a severe defect in complex III of the electron transport chain has been examined by 3tp NMR measurements of the molar ratio of phosphocreatine to inorganic phosphate (PCr/Pi). Resting ratios were 1.3-2.5, which can be compared with roughly 8.6 for a young, normal female control at rest. Quantitative evaluation of the activity of oxidative metabolism was afforded by the rate of recovery of PCr/P, from exercise and was found to be 2.5% of normal. After administration of menadione and ascorbate, we found a 21-fold increase of the recovery rate relative to the pretherapy value, to within 56% of the recovery rate of the young female control. Thus, NMR examinations of skeletal muscle at rest and in recovery from activity document marked improvement to specific drug therapy in the electron transport capabilities and the ATP synthesis rate of a patient with a deficiency in a cytochrome b-containing complex III. Improvements in functional ability, although not as dramatic as biochemical changes, are also apparent.NMR examination of excised skeletal muscle in vitro has enabled us to define limits to the thermodynamically related parameter of the molar ratio of phosphocreatine to inorganic phosphate (PCr/Pi) from its maximum >10 at rest (state 4) to a value of 1 for fully activated (state 3) oxidative metabolism, beyond which the activation of glycolytic energy metabolism causes severe tissue lactic acidosis. Similar observations of the human arm during measured exercise using a Cybex isokinetic ergometer and phosphorus NMR determination of PCr/Pj indicate that the ratio of energy expenditure to work output is approximately constant from the resting (state 4) to the maximally "aerobic" contracting muscle (state 3) (1). Human in vivo NMR spectroscopy has offered quantitation of energy performance in naive and trained skeletal muscle of the arm and the leg (2) as well as evidence of deficient oxygen supply to calf muscle in peripheral vascular disease (3,4). Similar studies have been performed on several inborn errors of metabolism, including McArdle disease (5), phosphofructokinase deficiency (3, 6), and an idiopathic cardiomyopathy (7). In moderate peripheral vascular disease and some metabolic diseases, oxygen delivery and tissue metabolism appear sufficient to allow adequate tissue level of ATP to maintain PCr/Pj > 2 with a correspondingly adequate thermodynamic capability.To quantitate the limits of PCr/Pj and improve the functional capability of patients with bioenergetic disabilities, we have studied the resting and limited-activity states of a patient with a deficiency of several polypeptides of complex III, including reducible cytochrome b, and greatly diminished ubiquinol-cytochrome c reductase activity. In attempting to improve the patient's thermodynamic capabilities by increasing the resting levels of PCr/Pj and accelerating recovery times, we have designed an appropriate bypass of the cytochrome b-deficient sites by redox mediato...

Electron‐transfer restoration by vitamin K3 in a complex III‐deficient mutant of S. cerevisiae and sequence of the corresponding cytochrome b mutation

“…The possibility of improving oxidative phosphorylation has been investigated in this patient using therapeutic agents which bypass the cytochrome-deficient site. Therapy with menadione and ascorbate was found to improve phosphorylation in the patient, and concomitantly to somewhat improve the functional activity [5].…”

“…The complex IIIdeficient patient has been favorably treated with vitamins K3 and C and the rationale for this drug therapy was based on known in vitro results with antimycin-inhibited yeast [5].…”

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

“…Clinical investigations of methylene blue as a treatment for AD have not been conducted. Menadione and ascorbate together can act as complex IV substrates and sustain mitochondrial ETC respiration when complex III is compromised [79]. Other compounds that enhance mitochondrial ETC and oxidative phosphorylation include nicotinamide, a precursor to the complex I substrate, nicotinamide adenine dinucleotide, and riboflavin, a precursor to the complex II substrate, flavin adenine dinucleotdie [84].…”

An alternative, non-intrauterine hypothesis, based on maternal mitochondrial oocyte inheritance, to explain inconsistent findings of birth weight on (breast) cancer risk

“…In *Correspondence: PAH van Noord; E-mail: P.A.H.vanNoord@jc.azu.nl www.bjcancer.com addition to sufficient calories (glucose), there is evidence for a role of other essential nutrients on the proper functioning of the respiratory enzymes of the mitochondrial membrane-bound Kreb's cycle. Such nutrients can mend deficiencies, either in specific diseases (Eleff, 1984) or enzyme deficiencies accumulating with age(ing) (Ames, 2002). Suboptimal energy production by less viable mitochondria may, for example, affect the correct functioning of the cell spindle required for proper chromosome separation during these first five cell divisions, resulting either in abortion or when the fertilized egg survives, aneuploidy in the foetus and related birth defects.…”