The Evidence Base

Peer-reviewed studies, open-access preprints, and regulatory documents — organized by mechanism, not organ system. Because the biology does not respect specialty boundaries, and neither should the evidence.

2 open-access Zenodo publications by Johanna Ihli, BSN

Latest review published as an open-access Zenodo preprint

FDA Docket FDA-2026-P-5116 on record

Published Work — DIMD Initiative

Open-Access Publications & Regulatory Filings

Open-Access Preprint · Zenodo · 2026

A Systems-Level Disease Model of Drug-Induced Mitochondrial Dysfunction (DIMD): Integrating Delayed Multisystem Toxicity Through Modern Mitochondrial Biology and Pharmacovigilance

Johanna Ihli, BSN · Zenodo, May 26, 2026 (v3) · Open Access · Revised disease-model preprint

This revised preprint formally proposes DIMD as an acquired, exposure-associated, systems-level disease model capable of producing delayed, multisystem, and potentially persistent clinical manifestations. It presents FQAD as a clinically and regulatorily documented prototype subtype and integrates modern mitochondrial biology with pharmacovigilance limitations. This is the current conceptual and mechanistic foundation of the DIMD initiative.

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Version DOI: 10.5281/zenodo.20399689 · All-versions DOI: 10.5281/zenodo.20006893

Open-Access Publication · Zenodo

Drug-Induced Mitochondrial Dysfunction: Mechanisms, Persistence, and Challenges for Pharmacovigilance

Johanna Ihli, BSN · Zenodo, March 25, 2026 (v3) · CC BY 4.0

Reviews the mechanistic basis of drug-induced mitochondrial injury, the evidence for persistence beyond drug clearance, and the structural gaps in current pharmacovigilance frameworks that prevent recognition and tracking of delayed mitochondrial adverse effects.

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DOI: 10.5281/zenodo.19224996

FDA Citizen Petition · 2026

Citizen Petition Regarding Enhanced Informed Consent for Systemic Fluoroquinolone Antibiotics

Accepted for filing. Docket FDA-2026-P-5116. Open for public comment on regulations.gov. Requests updated informed consent language and improved patient-facing risk communication. CC BY 4.0.

Read Petition · DOI: 10.5281/zenodo.20128765

Open-Access Preprint · Updated May 2026

Systems-Level DIMD Disease Model — Revised Preprint (v3)

Following submission to Drug Safety and editorial transfer to the European Journal of Medical Research, the revised disease-model manuscript is now publicly available on Zenodo. It proposes DIMD as an exposure-associated systems-level disease model and presents FQAD as the prototype subtype.

Read Revised Preprint · DOI: 10.5281/zenodo.20399689

ORCID · Verified Researcher

Johanna Ihli, BSN — ORCID Profile

All published work is associated with a verified ORCID identifier. ORCID provides a persistent digital identifier that distinguishes researchers and connects them to their contributions.

ORCID: 0009-0008-1486-7242

Reference Library

Peer-Reviewed Literature by Mechanism

Organization note: References are organized by mechanistic domain rather than organ system — reflecting the systems-level nature of drug-induced mitochondrial dysfunction. A study about mitochondrial ROS in neuronal cells and a study about tendon injury share a mechanistic root; separating them by organ would obscure the connection the DIMD framework is built to reveal. Key references are highlighted. References marked with ★ are particularly central to the DIMD evidence base.

Foundational Mito Biology mtDNA Injury & Energy Failure Fluoroquinolone Mechanisms Delayed & Progressive Injury Topoisomerase & Crosswalk Broader DIMD Framework

Section I — Foundational Mitochondrial Biology & Drug Toxicology

Core literature establishing mitochondria as pharmacological targets and the theoretical basis for drug-induced mitochondrial injury

Wallace KB, Starkov AA.
★ Foundational
Mitochondrial targets of drug toxicity.
Annual Review of Pharmacology and Toxicology. 2000;40:353–388.
Seminal review establishing the mechanistic basis for mitochondria as targets of drug toxicity. Foundational to the entire DIMD framework.

Nadanaciva S, Will Y.

Pharmacology

Investigating mitochondrial dysfunction to increase drug safety in the pharmaceutical industry.

Current Drug Targets. 2011;12(6):774–786.

Dykens JA, Will Y.

The significance of mitochondrial toxicity testing in drug development.

Drug Discovery Today. 2007;12(17–18):777–785.

Gray MW.

Mitochondrial evolution.

Science. 1999;283(5407):1476–1481.

Neustadt J, Pieczenik SR.
★ Foundational Review
Medication-induced mitochondrial damage and disease.
Molecular Nutrition & Food Research. 2008;52:780–788.
Foundational review linking multiple medication classes to mitochondrial damage, multisystem disease presentation, reactive oxygen species generation, and feed-forward injury loops. Notably documented that mitochondrial toxicity testing was not required for FDA drug approval at the time of publication — an early articulation of the regulatory gap the DIMD framework addresses. Covers psychotropic drugs, statins, analgesics, antiretrovirals, antibiotics, and many others. Directly supports the breadth of the DIMD public health argument.

Section II — Mechanisms: mtDNA Injury, Oxidative Stress & Energy Failure

Literature on the specific intracellular mechanisms by which drugs impair mitochondrial DNA, electron transport, and cellular energy production

Meyer JN, et al.

Mitochondrial toxicity of environmental chemicals and pharmaceuticals.

Toxicology. 2013;313(2–3):66–73.

Scatena R.

Mitochondria and drugs.

Advances in Experimental Medicine and Biology. 2012;942:329–346.

Boelsterii UA, Lim PL.

Mitochondrial abnormalities — a link to idiosyncratic drug hepatotoxicity?

Toxicology and Applied Pharmacology. 2007;220(1):92–107.

Kuretu A, Mothibe M, Ngubane P, Sibiya N.

Elucidating the effect of drug-induced mitochondrial dysfunction on insulin signaling and glucose handling in skeletal muscle cell line (C2C12) in vitro.

PLoS ONE. 2024;19(9):e0310406.

Section III — Fluoroquinolone-Specific Mechanisms

Molecular pharmacology of fluoroquinolone mitochondrial toxicity — from topoisomerase inhibition to the newly confirmed AIFM1 and IDH2 off-targets

Reinhardt T, El Harraoui Y, Rothemann A, Jauch AT, Müller-Deubert S, Köllen MF, et al.
★ Key · 2025
Chemical proteomics reveals human off-targets of fluoroquinolone-induced mitochondrial toxicity.
Angewandte Chemie International Edition. 2025;64(18):e202421124.
Landmark chemical proteomics study confirming AIFM1 and IDH2 as validated direct off-targets of fluoroquinolone binding in human cells, with downstream downregulation of mitochondrial Complexes I and IV. Directly validates two of the four multi-hit insults in the DIMD mechanistic framework. This is the molecular foundation beneath thirty years of clinical observation.

Hooper DC.

Mechanisms of action of antimicrobials: focus on fluoroquinolones.

Clinical Infectious Diseases. 2001;32(Suppl 1):S9–S15.

Lawrence JW, Claire DC, Weissig V, Rowe TC.
★ Foundational
Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells.
Molecular Pharmacology. 1996;50(5):1178–1188.
Early experimental evidence that ciprofloxacin cleaves mitochondrial DNA in mammalian cells — demonstrating that the antibiotic's effects on mtDNA were not theoretical but measurable. Published nearly thirty years before Reinhardt 2025 confirmed the protein-level mechanism.

Kalghatgi S, Spina CS, Costello JC, et al.
★ Key
Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in mammalian cells.
Science Translational Medicine. 2013;5(192):192ra85.
Demonstrated that bactericidal antibiotics — including fluoroquinolones — induce mitochondrial dysfunction and oxidative damage in mammalian cells, independent of their antibacterial mechanism. One of the most-cited studies in the FQ mitochondrial toxicity literature.

Kaufmann P, Török M, Zahno A, et al.

Toxicity of fluoroquinolones: oxidative stress and mitochondrial damage.

Toxicology. 2011;279(1–3):1–6.

Hangas A, et al.

Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of topoisomerase 2.

Nucleic Acids Research. 2018;46(18):9625–9636.

Pieper S.

Fluoroquinolone-Associated Disability (FQAD) — Pathogenesis, Diagnostics, Therapy and Diagnostic Criteria.

Springer; 2021.

Section IV — Clinical Pattern: Delayed & Progressive Injury

Epidemiological and clinical evidence for delayed, persistent, and potentially permanent adverse effects following fluoroquinolone exposure

Baxter R, Ray GT, Fireman BH.
★ Clinical
Case-control study of fluoroquinolone use and risk of Achilles tendon rupture.
American Journal of Medicine. 2008;121(3):241–247.
Large case-control study establishing the epidemiological link between fluoroquinolone use and Achilles tendon rupture — the clinical signal that drove the 2008 FDA boxed warning.

Pereira CV, et al.

Drug-induced mitochondrial dysfunction and toxicity: from bench to bedside.

Expert Opinion on Drug Metabolism & Toxicology. 2009;5(5):1–15.

Section V — Mechanistic Crosswalk: Topoisomerase Inhibition

Literature bridging fluoroquinolone and chemotherapy toxicology through the shared mechanism of topoisomerase inhibition

Pommier Y.

Topoisomerase I and II in cancer chemotherapy: update and perspectives.

Nature Reviews Cancer. 2010;10(10):690–702.

Foundational review of topoisomerase inhibition in chemotherapy — relevant to the DIMD framework because fluoroquinolones share the topoisomerase inhibition mechanism with established chemotherapeutic agents known to cause mitochondrial and organ toxicity.

Section VI — Mitochondrial Vulnerability as Broader DIMD Framework Support

Independent lines of evidence from unrelated research groups demonstrating that mitochondrial vulnerability is a real, measurable, clinically relevant risk factor — supporting the DIMD framework's central argument

Mori G, Yamamoto M, Ishikawa K, Tamashiro H, Suzuki H, Mizuno S, Nakada K, Kawaguchi A.
★ Key · 2026Article in Press
Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.
Nature Communications. 2026. DOI: 10.1038/s41467-026-71295-1. Article in Press (accepted March 18, 2026). CC BY-NC-ND 4.0. University of Tsukuba, Japan.
A completely independent research group studying a completely different exposure — mRNA vaccination — demonstrated that subclinical mitochondrial vulnerability, compensated and clinically silent at baseline, can be unmasked by biological stress, triggering cardiac dysfunction through mitochondrial ROS and necroptosis. This is precisely the DIMD framework's central argument applied by an independent team to an independent context: pre-existing mitochondrial vulnerability is a hidden risk factor that standard safety evaluation does not account for.

The Evidence Is Here. The Gap Is Documented. Now We Act.

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