Runaway uncoupling in 2,4-dinitrophenol poisoning : Clinical and mitochondrial observations from two cases
Lindeman, Erik ; Sommer, Tine ; Leffler, Märta LU
; Sekine, Shusuke
LU
; Elmér, Eskil
LU
; Sjövall, Fredrik
LU
and Wallquist, Wilhelm
LU
(2025)
In Toxicology Reports
16.
- Abstract
2,4-Dinitrophenol (DNP) is a potent mitochondrial uncoupler briefly marketed in the 1930s as a weight-reducing agent before being banned by the FDA after reports of severe toxicity. Since the early 2000s, DNP has reemerged as an illicit "fat-burner", causing characteristic metabolic disturbances with a high risk of fatal outcome. We describe two Swedish cases of DNP poisoning: one fatal after suicidal ingestion and one non-fatal after use for weight reduction. Clinical data, mitochondrial respirometry, and analysis of gas exchange and ventilatory dynamics were used to characterize the metabolic disturbances under intensive care. The fatal case progressed within hours to respiratory acidosis, hyperthermia, severe hyperkalemia, and... (More)
2,4-Dinitrophenol (DNP) is a potent mitochondrial uncoupler briefly marketed in the 1930s as a weight-reducing agent before being banned by the FDA after reports of severe toxicity. Since the early 2000s, DNP has reemerged as an illicit "fat-burner", causing characteristic metabolic disturbances with a high risk of fatal outcome. We describe two Swedish cases of DNP poisoning: one fatal after suicidal ingestion and one non-fatal after use for weight reduction. Clinical data, mitochondrial respirometry, and analysis of gas exchange and ventilatory dynamics were used to characterize the metabolic disturbances under intensive care. The fatal case progressed within hours to respiratory acidosis, hyperthermia, severe hyperkalemia, and peri-mortem rigidity consistent with catastrophic ATP depletion. The non-fatal case showed similar but reversible toxicity, with sustained yet manageable hypermetabolism lasting more than a week. Serial platelet respirometry demonstrated a marked initial increase in uncoupled respiration, followed by a progressive decline with a functional half-life of 4.9 days. Together, these cases suggest a self-amplifying feedback loop central to DNP toxicity, in which excessive CO₂ production from mitochondrial uncoupling causes local acidosis that enhances mitochondrial DNP uptake. Glucose supplementation and hyperkalemia management are essential supportive measures, whereas active cooling and high minute ventilation may blunt this self-reinforcing metabolic acceleration. Severe poisoning may result in a state of "runaway uncoupling," a term we propose for the catastrophic progression to death observed in numerous DNP poisonings. This feedback loop illustrates the unpredictable toxicokinetics of DNP and reinforces the FDA's early conclusion: DNP is "unfit for human consumption".
(Less)
- author
- Lindeman, Erik
; Sommer, Tine
; Leffler, Märta
LU
; Sekine, Shusuke
LU
; Elmér, Eskil
LU
; Sjövall, Fredrik
LU
and Wallquist, Wilhelm
LU
- organization
- publishing date
- 2025-12-08
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Toxicology Reports
- volume
- 16
- article number
- 102183
- publisher
- Elsevier
- external identifiers
-
- scopus:105024573668
- pmid:41487961
- ISSN
- 2214-7500
- DOI
- 10.1016/j.toxrep.2025.102183
- language
- English
- LU publication?
- yes
- additional info
- © 2025 The Authors.
- id
- 3a2d8cba-7b51-41b6-8c30-a84d151507c6
- date added to LUP
- 2026-01-08 14:10:34
- date last changed
- 2026-01-14 15:14:02
@article{3a2d8cba-7b51-41b6-8c30-a84d151507c6,
abstract = {{<p>2,4-Dinitrophenol (DNP) is a potent mitochondrial uncoupler briefly marketed in the 1930s as a weight-reducing agent before being banned by the FDA after reports of severe toxicity. Since the early 2000s, DNP has reemerged as an illicit "fat-burner", causing characteristic metabolic disturbances with a high risk of fatal outcome. We describe two Swedish cases of DNP poisoning: one fatal after suicidal ingestion and one non-fatal after use for weight reduction. Clinical data, mitochondrial respirometry, and analysis of gas exchange and ventilatory dynamics were used to characterize the metabolic disturbances under intensive care. The fatal case progressed within hours to respiratory acidosis, hyperthermia, severe hyperkalemia, and peri-mortem rigidity consistent with catastrophic ATP depletion. The non-fatal case showed similar but reversible toxicity, with sustained yet manageable hypermetabolism lasting more than a week. Serial platelet respirometry demonstrated a marked initial increase in uncoupled respiration, followed by a progressive decline with a functional half-life of 4.9 days. Together, these cases suggest a self-amplifying feedback loop central to DNP toxicity, in which excessive CO₂ production from mitochondrial uncoupling causes local acidosis that enhances mitochondrial DNP uptake. Glucose supplementation and hyperkalemia management are essential supportive measures, whereas active cooling and high minute ventilation may blunt this self-reinforcing metabolic acceleration. Severe poisoning may result in a state of "runaway uncoupling," a term we propose for the catastrophic progression to death observed in numerous DNP poisonings. This feedback loop illustrates the unpredictable toxicokinetics of DNP and reinforces the FDA's early conclusion: DNP is "unfit for human consumption".</p>}},
author = {{Lindeman, Erik and Sommer, Tine and Leffler, Märta and Sekine, Shusuke and Elmér, Eskil and Sjövall, Fredrik and Wallquist, Wilhelm}},
issn = {{2214-7500}},
language = {{eng}},
month = {{12}},
publisher = {{Elsevier}},
series = {{Toxicology Reports}},
title = {{Runaway uncoupling in 2,4-dinitrophenol poisoning : Clinical and mitochondrial observations from two cases}},
url = {{http://dx.doi.org/10.1016/j.toxrep.2025.102183}},
doi = {{10.1016/j.toxrep.2025.102183}},
volume = {{16}},
year = {{2025}},
}