In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to anoxia-reoxygenation, inhibition of the Krebs cycle at the level of malate dehydrogenase-2 (MDH-2) decreases hypoxia-inducible factor-1α and oxidative stress and protects from apoptotic or ferroptotic cell death. Reactive oxygen species (ROS) production causes cell death or senescence. Ischemia-reperfusion injury is the leading cause of acute kidney injury. Additionally, milk lactose concentrations suggest that MAP reduces the availability of lactose derivatives. The targeted metabolites were suggestive of wider changes in the bioenergetic metabolism that appear to be an acceleration of the effects of progressing lactation in healthy cows. Pearson's correlation analysis indicated relationships between milk lactose concentrations in mid-lactation and 6 metabolites that were tentatively linked to MAP-infection status. Pathway enrichment analysis suggested that MAP affected the malate-aspartate shuffle during early lactation. Examining each lactation stage separately for changes associated to MAP-infection status identified 45 metabolites, 33 in early lactation and 12 in mid-lactation, but only 6 metabolites were targeted in both stages of lactation. Metabolite fingerprinting assessments using partial least squares discriminate analyses (PLS-DA) indicated that lactation stage was a larger source of variation than MAP status. The milk metabolome was assessed using flow infusion electrospray high-resolution mass spectrometry (FIE-HRMS) for sensitive, non-targeted metabolite fingerprinting. The study used biobanked milk samples which were collected 73.4 ± 3.79 (early lactation) and 143 ± 3.79 (mean ± SE) (mid-lactation) days post-calving from 5 MAP-infected and 5 control multiparous cows. Herein, we examine the milk metabolomic profiles of naturally MAP-infected Holstein-Friesian cows. Infected cows begin shedding MAP within the asymptomatic, subclinical stage of infection before clinical signs, such as weight loss, diarrhoea and reduced milk yields develop within the clinical stages of disease. Mycobacterium avium subspecies paratuberculosis (MAP) is the causative organism of Johne's Disease, a chronic intestinal infection of ruminants. This illustrates the vitality of ongoing MAS research. The year 2019 saw the discovery of two new inborn errors in the MAS, deficiencies in malate dehydrogenase 1 and in aspartate transaminase 2 (GOT2). Most recently, the focus has been on the role of the MAS in tumors, on cells with defects in mitochondria and on inborn errors in the MAS. The MAS is still a very active field of research. This makes the MAS in practice uni-directional toward oxidation of cytosolic NADH, and explains why the free NADH/NAD ratio is much higher in the mitochondria than in the cytosol. Only in the 1970s, LaNoue and coworkers discovered that the efflux of aspartate from mitochondria, an essential step in the MAS, is dependent on the proton-motive force generated by the respiratory chain: for every aspartate effluxed, mitochondria take up one glutamate and one proton. The MAS was soon adopted in the field as a major pathway for NADH oxidation in mammalian tissues, such as liver and heart, even though the energetics of the MAS remained a mystery. The MAS was initially proposed as a route for the oxidation of cytosolic NADH by the mitochondria in Ehrlich ascites cell tumor lacking other routes, and to explain the need for a mitochondrial aspartate aminotransferase (glutamate oxaloacetate transaminase 2 ). This article presents a personal and critical review of the history of the malate-aspartate shuttle (MAS), starting in 1962 and ending in 2020.
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