Metabolism and mitochondrial dysfunction are known to be involved in many different disease states. We have employed two-photon fluorescence imaging of intrinsic mitochondrial reduced nicotinamide adenine dinucleotide (NADH) to quantify the metabolic state of several cultured cell lines, multicell tumor spheroids, and the intact mouse organ of Corti. Historically, fluorescence intensity has commonly been used as an indicator of the NADH concentration in cells and tissues. More recently, fluorescence lifetime imaging has revealed that changes in metabolism produce not only changes in fluorescence intensity, but also significant changes in the lifetimes and concentrations of free and enzyme-bound pools of NADH. Since NADH binding changes with metabolic state, this approach presents a new opportunity to track the cellular metabolic state.

The phenomenon known as the lactate paradox has been a topic of heated debate since it gained worldwide attention following Operation Everest in the early 1980s. What began as the simple finding that blood lactate (blood [La]) for a given sub-maximal workload or VO2 following acclimatization to high altitude is reduced compared with sea-level values, morphed into a complex set of parameters that have been redefined several times in the nearly 30 years that the lactate paradox has been researched. Though several strong hypotheses have been proposed to, to date, no one hypothesis has been able fully to explain the lactate paradox. The goal of the current article was to bring together the most prominent studies done on the lactate paradox and illuminate the details brought forth by each. In doing so we hope to stimulate new hypotheses and research studies that will further our understanding of the lactate paradox.

Reductive stress, characterised by an increased NADH:NAD+ ratio, may be as common and as important a consequence of redox imbalance as oxidative stress. It may also be an important predisposing cause of the generation of reactive oxygen species. Considerable experimental and indirect clinical evidence suggests that protection against reductive stress depends on biomolecules with electrophilic methyl groups (EMG) such as S-adenosylmethionine, betaine, carnitine and phosphatidylcholine. Pathological processes leading to reductive stress and their relief by such protective agents is reviewed and the proposed molecular mechanism is outlined. These and other EMG-containing biomolecules are part of the daily diet and may represent an important control system for redox balance.