Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk.

Chuan Wang,Jane F Ferguson,M Wade Calcutt

doi:10.3389/fendo.2021.710698

Abstract

Cardiometabolic disease affects the majority of individuals worldwide. The metabolite α-aminoadipic acid (2-AAA) was identified as a biomarker of Type 2 Diabetes (T2D). However, the mechanisms underlying this association remain unknown. DHTKD1, a central gene in the 2-AAA pathway, has been linked to 2-AAA levels and metabolic phenotypes. However, relatively little is known about its function. Here we report that DHTKD1 knock-out (KO) in HAP-1 cells leads to impaired mitochondrial structure and function. Despite impaired mitochondrial respiration and less ATP production, normal cell proliferation rate is maintained, potentially through a series of compensatory mechanisms, including increased mitochondrial content and Akt activation, p38, and ERK signaling. Common variants in DHTKD1 associate with Type 2 Diabetes and cardiometabolic traits in large genome-wide associations studies. These findings highlight the vital role of DHTKD1 in cellular metabolism and establish DHTKD1-mediated mitochondrial dysfunction as a potential novel pathway in cardiometabolic disease.

Highlights

The incidence of Type 2 Diabetes (T2D) has doubled over the past twenty years and affects over 425 million people globally [1,2,3], and is the 8th leading cause of death [4]
We examined the role of dehydrogenase E1 and transketolase domain containing 1 (DHTKD1) on mitochondrial function, and identified mechanisms linking DHTKD1 to oxidative phosphorylation (OXPHOS) and energy metabolism
There was a significant increase (P=0.002) in 2-AAA in the media of KO cells compared with WT (Figure 1C), consistent with absence of DHTKD1 activity to catabolize 2-AAA

Summary

Introduction

The incidence of Type 2 Diabetes (T2D) has doubled over the past twenty years and affects over 425 million people globally [1,2,3], and is the 8th leading cause of death [4]. T2D is associated with high mortality and incidence of comorbidities [5], including coronary artery disease, stroke, and peripheral artery disease [6]. There is some basic understanding of disease pathophysiology, the specific causes of T2D are often unknown. A broader and more in-depth understanding of molecular pathways associated with T2D is urgently needed. In recent years, studying metabolites and their signaling pathways as disease biomarkers and mediators has become a promising avenue of discovery

Methods

Results

Conclusion