Differential Nucleotide Inhibition Profile of Mouse and Human UCP1 Expressed in Liver Mitochondria Is Associated with an F88S Mutation

Verdict. Therefore, we expressed human and mouse UCP1 in mouse liver, using adeno-associated viral vectors, and characterized their properties in isolated liver mitochondria. It intersects mitochondrial stress/dysfunction themes (bioenergetics; OXPHOS / ETC).

What the authors report

Uncoupling protein 1 (UCP1) mediates thermogenesis in brown adipose tissue. Whether human-UCP1 shares the bioenergetic properties established for rodent UCP1 (innate uncoupling, GDP sensitivity, fatty acid (re)activation) is not known.

Key results stated in the abstract include the following. Therefore, we expressed human and mouse UCP1 in mouse liver, using adeno-associated viral vectors, and characterized their properties in isolated liver mitochondria. Both UCP1s induced marked innate uncoupling, characterized by increased substrate-supported respiration and decreased membrane potential, in the absence of exogenous fatty acids. Despite substantial UCP1-mediated uncoupling, oxidative phosphorylation capacity and mitochondrial OXPHOS protein levels were preserved.

Why it matters for mitochondrial biology

Within mitochondrial research, this work maps primarily to OXPHOS, mitochondrial dynamics, metabolism, structural biology. It is relevant to mitochondrial dysfunction discourse because the abstract invokes bioenergetics, OXPHOS / ETC. That does not by itself establish a validated disease mechanism; it indicates thematic proximity. OXPHOS/ETC involvement, if confirmed, would place the work in the core of bioenergetic pathophysiology rather than peripheral organelle biology. Server: biorxiv. Posted 2026-08-20. Synthesis confidence is bounded by abstract completeness.

Study design (abstract-level)

The abstract does not cleanly separate methods from results. Treat design details as incomplete until the full preprint is inspected.

Principal findings

1. Therefore, we expressed human and mouse UCP1 in mouse liver, using adeno-associated viral vectors, and characterized their properties in isolated liver mitochondria.
2. Both UCP1s induced marked innate uncoupling, characterized by increased substrate-supported respiration and decreased membrane potential, in the absence of exogenous fatty acids.
3. Despite substantial UCP1-mediated uncoupling, oxidative phosphorylation capacity and mitochondrial OXPHOS protein levels were preserved.
4. In-silico substitution of F88 by serine reduced GDP interaction at this site.
5. The F88/S88 difference may contribute to the preferential GDP sensitivity of mouse-UCP1, whereas ATP provides effective nucleotide control of human-UCP1.

Limitations of this brief

• This Mitos brief is an abstract-level synthesis of a preprint; it is not peer review and not a substitute for reading the full paper.
• Preprint status: findings may change with revision or journal review.
• Effect sizes, n numbers, statistics, and full experimental controls are typically incomplete at abstract resolution.
• Primary source: biorxiv DOI 10.64898/2026.08.19.745785 (posted 2026-08-20).

Open scientific questions

• Which specific experimental panels in the full paper establish the strongest causal claim, and how robust are the controls?
• Are OXPHOS defects primary drivers or secondary consequences of broader cellular stress?
• How do these findings sit relative to prior literature on the same pathway—replication, contradiction, or incremental extension?

Bottom line

For mitochondrial biologists focused on OXPHOS, mitochondrial dynamics, metabolism, this preprint is worth full-text review soon. Abstract-level takeaway: Therefore, we expressed human and mouse UCP1 in mouse liver, using adeno-associated viral vectors, and characterized their properties in isolated liver mitochondria. Confirm methods, effect sizes, and controls in the full PDF before citing the result as established.

Bibliographic record

Abstract-based editorial synthesis by Mitos. Not peer review.