bims-fatoxi 2024-03-17 papers

Issue of 2024–03–17
five papers selected by
Shashwat Sharma, Deakin University

Res Sq. 2024 Feb 29. pii: rs.3.rs-3980524. [Epub ahead of print]

Structural Basis for Expanded Substrate Specificities of Human Long Chain Acyl-CoA Dehydrogenase and Related Acyl- CoA Dehydrogenases.

Beena Narayanan, Chuanwu Xia, Ryan McAndrew, Anna L Shen, Jung-Ja P Kim.

Crystal structures of human long-chain acyl-CoA dehydrogenase (LCAD) and the E291Q mutant, have been determined. These structures suggest that LCAD harbors functions beyond its historically defined role in mitochondrial β-oxidation of long and medium-chain fatty acids. LCAD is a homotetramer containing one FAD per 43kDa subunit with Glu291 as the catalytic base. The substrate binding cavity of LCAD reveals key differences which makes it specific for longer and branched chain substrates. The presence of Pro132 near the start of the E helix leads to helix unwinding that, together with adjacent smaller residues, permits binding of bulky substrates such as 3α, 7α, l2α-trihydroxy-5β-cholestan-26-oyl-CoA. This structural element is also utilized by ACAD11, a eucaryotic ACAD of unknown function, as well as bacterial ACADs known to metabolize sterol substrates. Sequence comparison suggests that ACAD10, another ACAD of unknown function, may also share this substrate specificity. These results suggest that LCAD, ACAD10, ACAD11 constitute a distinct class of eucaryotic acyl CoA dehydrogenases.

DOI: https://doi.org/10.21203/rs.3.rs-3980524/v1

Mol Genet Metab Rep. 2024 Mar;38 101061

Stealthy progression of type 2 diabetes mellitus due to impaired ketone production in an adult patient with multiple acyl-CoA dehydrogenase deficiency.

Nodoka Ikeda, Yoichi Wada, Tomohito Izumi, Yuichiro Munakata, Hideki Katagiri, Shigeo Kure.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disorder caused by biallelic pathogenic variants in genes related to the flavoprotein complex. Dysfunction of the complex leads to impaired fatty acid oxidation and ketone body production which can cause hypoketotic hypoglycemia with prolonged fasting. Patients with fatty acid oxidation disorders (FAODs) such as MADD are treated primarily with a dietary regimen consisting of high-carbohydrate foods and avoidance of prolonged fasting. However, information on the long-term sequelae associated with this diet have not been accumulated. In general, high-carbohydrate diets can induce diseases such as type 2 diabetes mellitus (T2DM), although few patients with both MADD and T2DM have been reported.
Case: We present the case of a 32-year-old man with MADD who was on a high-carbohydrate diet for >30 years and exhibited symptoms resembling diabetic ketoacidosis. He presented with polydipsia, polyuria, and weight loss with a decrease in body mass index from 31 to 25 kg/m2 over 2 months. Laboratory tests revealed a HbA1c level of 13.9%; however, the patient did not show metabolic acidosis but only mild ketosis.
Discussion/conclusion: This report emphasizes the potential association between long-term adherence to high-carbohydrate dietary therapy and T2DM development. Moreover, this case underscores the difficulty of detecting diabetic ketosis in patients with FAODs such as MADD due to their inability to produce ketone bodies. These findings warrant further research of the long-term complications associated with this diet as well as warning of the potential progression of diabetes in patients with FAODs such as MADD.

Keywords: Diabetic ketoacidosis; Multiple acyl-CoA dehydrogenase deficiency; Type 2 diabetes mellitus

DOI: https://doi.org/10.1016/j.ymgmr.2024.101061

J Bone Miner Res. 2024 Mar 05. pii: zjae034. [Epub ahead of print]

FATP2 regulates Osteoclastogenesis by increasing lipid metabolism and ROS production.

Xiangxi Kong, Siyue Tao, Zhongyin Ji, Jie Li, Hui Li, Jiayan Jin, Yihao Zhao, Junhui Liu, Fengdong Zhao, Jian Chen, Zhenhua Feng, Binhui Chen, Zhi Shan.

Lipid metabolism plays a crucial role in maintaining bone homeostasis, particularly in osteoclasts (OCs) formation. Here, we found the expression level of FATP2, a transporter for long-chain and very-long-chain fatty acids, was significantly upregulated during OC differentiation and in the bone marrow of mice fed a high-fat diet (HFD). Notably, the use of FATP2 siRNA or a specific inhibitor (Lipofermata) resulted in significant inhibition of OC differentiation while only slightly affecting osteoblasts (OBs). In pathological models of bone loss induced by LPS or OVX, in vivo treatment with Lipofermata was able to rescue the loss of bone mass by inhibiting OC differentiation. RNA sequencing (RNA-seq) revealed that Lipofermata reduced fatty acid β-oxidation and inhibited energy metabolism, while regulating reactive oxygen species (ROS) metabolism to decrease ROS production, ultimately inhibiting OC differentiation. Treatment with Lipofermata, either in vivo or in vitro, effectively rescued the overactivation of OCs, indicating that FATP2 regulated OC differentiation by modulating fatty acid uptake and energy metabolism. These findings suggested that targeting FATP2 may represent a promising therapeutic approach for pathological osteoporosis.

Keywords: FATP2; Lipid metabolism; Lipofermata; ROS; osteoclast

DOI: https://doi.org/10.1093/jbmr/zjae034

Int J Mol Sci. 2024 Feb 29. pii: 2835. [Epub ahead of print]25(5):

Mitochondria at the Nanoscale: Physics Meets Biology-What Does It Mean for Medicine?

Lev Mourokh, Jonathan Friedman.

Mitochondria are commonly perceived as "cellular power plants". Intriguingly, power conversion is not their only function. In the first part of this paper, we review the role of mitochondria in the evolution of eukaryotic organisms and in the regulation of the human body, specifically focusing on cancer and autism in relation to mitochondrial dysfunction. In the second part, we overview our previous works, revealing the physical principles of operation for proton-pumping complexes in the inner mitochondrial membrane. Our proposed simple models reveal the physical mechanisms of energy exchange. They can be further expanded to answer open questions about mitochondrial functions and the medical treatment of diseases associated with mitochondrial disorders.

Keywords: autism spectrum disorder; carcinogenesis; equations of motion; mitochondria; proton-pumping complex; respiratory transport chain

DOI: https://doi.org/10.3390/ijms25052835

J Biol Chem. 2024 Mar 11. pii: S0021-9258(24)01654-5. [Epub ahead of print] 107159

Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase.

Cathryn Grayson, Ben Faerman, Olivia Koufos, Ryan J Mailloux.

In the present study, we examined the mitochondrial hydrogen peroxide (mH2O2) generating capacity of α-ketoglutarate dehydrogenase (KGDH) and compared it to components of the electron transport chain (ETC) using liver mitochondria isolated from male and female C57BL6N mice. We show for the first time there are some sex dimorphisms in the production of mH2O2 by ETC complexes I and III when mitochondria are fueled with different substrates. However, in our investigations into these sex effects, we made the unexpected discovery that: 1. KGDH serves as a major mH2O2 supplier in male and female liver mitochondria and 2. KGDH can form mH2O2 when mitochondria are energized with fatty acids, but only when malate is used to prime the Krebs cycle. Surprisingly, 2-keto-3-methylvaleric acid (KMV), a site-specific inhibitor for KGDH, nearly abolished mH2O2 generation in both male and female liver mitochondria oxidizing palmitoyl-carnitine. KMV inhibited mH2O2 production in liver mitochondria from male and female mice oxidizing myristoyl-, octanoyl-, or butyryl-carnitine. S1QEL 1.1 (S1) and S3QEL 2 (S3), compounds that inhibit reactive oxygen species (ROS) generation by complexes I and III, respectively, without interfering with OxPhos, had a negligible effect on the rate of mH2O2 production when pyruvate or acyl-carnitines were used as fuels. However, inclusion of KMV in reaction mixtures containing S1 and/or S3 almost abolished mH2O2 generation. Together, our findings suggest KGDH is the main mH2O2 generator in liver mitochondria, even when fatty acids are used as fuel.

DOI: https://doi.org/10.1016/j.jbc.2024.107159