Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate

Abstract

Thioredoxin-interacting protein (TXNIP) is an α-arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes β-cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.

Gal-3 is a potential biomarker for spinal cord injury and Gal-3 deficiency attenuates neuroinflammation through ROS/TXNIP/NLRP3 signaling pathway

“…TXNIP is an important member of the body’s antioxidant stress response thioredoxin, mainly playing an oxidative stress role [24]. Recent studies have found that TXNIP can bind to and activate NLRP3 in a diseased state, thereby activating NLRP3 signaling pathway [22,24]. Our present data showed that Gal-3 regulates TXNIP/NLRP3 signaling pathway to promote neuroinflammation in SCI.…”

Effects of GH/IGF on the Aging Mitochondria

“…TXNIP knockout mice ( TXNIP KO) show impaired metabolic homeostasis, including adipogenesis and reduced gluconeogenesis [ 76 ], and decreased glucose uptake [ 77 ]. Similarly, a recently described human mutation demonstrated that diminished TXNIP function is linked to inefficient utilization of glucose [ 78 ]. Accordingly, glucose stress (hyperglycemia) upregulated TXNIP levels in 3T3LY adipocytes and was downregulated by IGF-1 and insulin ( Figure 5 A) [ 79 ].…”

<p>Thioredoxin-Interacting Protein as a Novel Potential Therapeutic Target in Diabetes Mellitus and Its Underlying Complications</p>

“…The α-arrestins are known as multifunctional scaffolding proteins involved in protein-protein interactions that mediate a wide array of signaling processes. 15 TXNIP is expressed in metabolically important sites like adipose tissue, liver, and skeletal muscles. It is also the main regulator of glucose balance in our system.…”