Draft:HEAT Cycle

• Comment: Interesting, however, it needs rewriting and multiple reliable source must be added Cinder painter (talk) 09:31, 2 June 2025 (UTC)

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HEAT Cycle in Brown Adipose Tissues

The HEAT Cycle is a proposed metabolic pseudo-futile cycle that occurs in the mitochondria of brown adipose tissue (BAT) and is essential for non-shivering thermogenesis. According to it, heat is generated through uncoupling protein 1 (UCP1), which uncouples protons from the electron transport chain (ETC). The primary fuel used in this process is Acetyl Coenzyme A (Acetyl-CoA). Acetyl-CoA enters the Krebs cycle, producing NADH and FADH2. These molecules then enter the electron transport chain to generate ATP. In cold-acclimated environments, instead of allowing protons from NADH and FADH2 to produce ATP, UCP1 uncouples these protons, resulting in heat production. The Acetyl-CoA is then recycled using NADPH and ATP, making it available for reuse. The cycle was first described in a 2021 study by Mirza et al. published in Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. The discovery emerged from comparative proteomics analysis of mitochondria from the brown fat of mice acclimated to different temperatures (30°C, 23°C, and 6°C) .

The HEAT Cycle is essentially a pseudo-futile cycle of fatty acid β-oxidation. Its proposed mechanism involves the continuous activation and de-activation of fatty acids within the mitochondria. Fatty acids are first activated by Acyl-CoA synthetases (ACSL1, ACSL5, ACSL6) to form Acyl-CoAs, which then enter the β-oxidation pathway. The central feature of the cycle is the de-activation of these Acyl-CoAs by the enzyme Acyl-CoA thioesterase 11 (ACOT11), releasing the fatty acid. This fatty acid is then immediately re-activated by Acyl-CoA synthetase family member 2 (ACSF2) to re-enter the cycle. The repeated consumption of ATP during the re-activation step, without the full breakdown of the fatty acid for energy, results in the net release of energy as heat. This specialized mechanism highlights a dedicated pathway for heat production in brown adipocytes, distinct from the uncoupling protein UCP1, and represents a significant potential pathway in cellular thermogenesis.

Detail of Experiment

In our recent study on differential temperature-based analysis of cytoplasmic mitochondria (CM) and lipid droplet-anchored mitochondria (LDAM), we observed that LDAM generate heat through uncoupling proteins, while CM not only produce heat but also enhance the overall cellular metabolism of brown fat cells (BFCs). It was noted that at lower temperatures, BFCs begin to generate heat at the indirect expense of ATP. Fatty acids are transported to mitochondria, where they are gradually broken down through the β-oxidation pathway, producing NADH and FADH2. NADH donates its protons to complex I (C-I) of the electron transport chain (ETC). The protons from NADH then move to ubiquinone, then to complex III (C-III), and finally to complex IV (C-IV), resulting in the production of water and ATP. ATP is synthesized by ATP synthase at each step of proton movement. Meanwhile, FADH donates its protons directly to C-III through ubiquinone in the ETC, also contributing to ATP and water production. It is known that in isolated mitochondrial samples of the ETC, 2.5 ATP molecules are produced from NADH and 1.5 ATP molecules from FADH . Uncoupling protein (UCP) disrupts the electron transport chain (ETC) by uncoupling protons, diverting them towards heat production instead of ATP synthesis. The glycerol-3-phosphate (G3P) shuttle has been shown to be active at lower temperatures; it transfers cytoplasmic NADH to the mitochondria in the form of FADH.