High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability

Metabolic reprogramming is a hallmark of cancer, with acute myeloid leukemia (AML) being no exception. Mitochondrial function, particularly its role in protecting tumor cells against chemotherapy, is of significant interest in AML chemoresistance. In this study, we identified mitochondrial DNA content (mtDNAc), measured by quantitative PCR, as a simple and precise marker to stratify the metabolic states of AML patients. We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation (OXPHOS), often correlating with chemoresistance. Clinically, patients receiving cytarabine and an anthracycline-based regimen (7 + 3 regimen) experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence. Ex vivo experiments using primary AML samples confirmed cytarabine resistance in high mtDNAc patients, which could be overcome by inhibiting mitochondrial complex I. The FDA-approved drug metformin, which targets mitochondrial metabolism, significantly enhanced apoptosis in response to chemotherapy or targeted agents, such as venetoclax, in AML models. However, metformin-treated cells adapted by increasing glycolysis and NAD<sup>+</sup> production, a resistance mechanism that could be bypassed by targeting the nicotinamide phosphoribosyltransferase (NAMPT) enzyme. In summary, we demonstrated that mtDNAc is an effective tool for assessing the metabolic state of AML cells. This method can be easily implemented in clinical practice to identify chemoresistant patients and guide personalized treatment strategies, including novel combination therapies for those with a high reliance on mitochondrial metabolism.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-07-13
DOI
https://doi.org/10.1038/s41392-025-02303-x
Citations
9
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
15.93

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article

High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability

Jan Jacob Schuringa, Isabel Weinhäuser, Dominique Sternadt, Emmanuel Griessinger et al.
9 citations
Signal Transduction and Targeted Therapy
Acute Myeloid Leukemia Research
15.93
article

High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability

Jan Jacob Schuringa, Isabel Weinhäuser, Dominique Sternadt, Emmanuel Griessinger, Amanda Moreira‐Aguiar, Lynn Swun Quek, Pedro L. Franca‐Neto, Eduardo Magalhães Rego, Nisha K van der Meer, Fabı́ola Traina, Marinus M Lima, Marcos Bezerra, Bruno Kosa Lino Duarte, Emanuele Ammatuna, Diego A. Pereira‐Martins, Douglas RA Silveira, Antônio Bruno Alves-Silva, Juan Luiz Coelho‐Silva, Ayşegül Erdem, Prodromos Chatzikyriakou, Jacobien R. Hilberink, Maria L. Salustiano-Bandeira, Gerwin A. Huls, Antonio R. Lucena-Araujo, Sara T.O. Saad
article en
9 citations

Abstract

Metabolic reprogramming is a hallmark of cancer, with acute myeloid leukemia (AML) being no exception. Mitochondrial function, particularly its role in protecting tumor cells against chemotherapy, is of significant interest in AML chemoresistance. In this study, we identified mitochondrial DNA content (mtDNAc), measured by quantitative PCR, as a simple and precise marker to stratify the metabolic states of AML patients. We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation (OXPHOS), often correlating with chemoresistance. Clinically, patients receiving cytarabine and an anthracycline-based regimen (7 + 3 regimen) experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence. Ex vivo experiments using primary AML samples confirmed cytarabine resistance in high mtDNAc patients, which could be overcome by inhibiting mitochondrial complex I. The FDA-approved drug metformin, which targets mitochondrial metabolism, significantly enhanced apoptosis in response to chemotherapy or targeted agents, such as venetoclax, in AML models. However, metformin-treated cells adapted by increasing glycolysis and NAD<sup>+</sup> production, a resistance mechanism that could be bypassed by targeting the nicotinamide phosphoribosyltransferase (NAMPT) enzyme. In summary, we demonstrated that mtDNAc is an effective tool for assessing the metabolic state of AML cells. This method can be easily implemented in clinical practice to identify chemoresistant patients and guide personalized treatment strategies, including novel combination therapies for those with a high reliance on mitochondrial metabolism.

Signal Transduction and Targeted TherapyVol. 10(1)
University Medical Center Groningen (NL), University of Groningen (NL), Universidade de São Paulo (BR), Universidade Estadual de Campinas (UNICAMP) (BR), King's College London (GB), Universidade Federal de Pernambuco (BR), Blood Cancer UK (GB), de Duve Institute (BE), Fundação de Amparo à Pesquisa do Estado de São Paulo (BR)
UK Research and Innovation, King's College London, Rijksuniversiteit Groningen, Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Universitair Medisch Centrum Groningen, Medical Research Council
Good health and well-being
Openalex Percentile: Top 1%
Acute Myeloid Leukemia Research
15.93
DOIOpen Access PDFOpenAlex
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