The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases

Abstract

Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.

Keywords: Aging; Cardiovascular diseases; Ketone body metabolism; Mitochondria.

Fig.1. Ketone body utilization

Ketone bodies are converted into acetyl-CoA and act as energy substrates by entering the TCA cycle. AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; βOHB, β-hydroxybutyrate; NAD, nicotinamide adenine dinucleotide; SCOT, succinyl-CoA:3-ketoacid CoA-transferase; TCA, tricarboxylic acid cycle

Fig.2. Ketone body production

HMG-CoA synthase 2 (Hmgcs2), a mitochondrion-localized protein, serves as the rate-limiting enzyme in ketone body synthesis. AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; βOHB, β-hydroxybutyrate; NAD, nicotinamide adenine dinucleotide

Fig.3. Loss of ketone body production impairs mitochondrial function

When ketogenesis is impaired, the substrate acetyl-CoA accumulates. This accumulated acetyl-CoA then leads to ectopic fat deposition through de novo lipogenesis, and within the mitochondria, excessive protein acetylation progresses, causing functional impairment. AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; βOHB, β-hydroxybutyrate; NAD, nicotinamide adenine dinucleotide

Fig.4. Multiple roles of ketone body metabolism

Ketone body metabolism has diverse functions beyond providing energy substrates; this includes signal transduction, epigenome regulation, and mitochondrial protection.