A Permeable Succinate Improved Platelet Mitochondrial Respiration in Paediatric Acute Lymphoblastic Leukaemia in Remission – Case Report
Permeable succinate improved platelet respiration in pediatric leukemia
Abstract
Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. In the last decades, the survival rate of paediatric patients diagnosed with ALL has been significantly improved due to standardised treatment protocols based on risk stratification. Platelet mitochondrial dysfunction has been recently reported to occur in most chronic diseases, including malignancies. Permeable succinate (NV118) is a novel mitochondria-targeted compound capable to alleviate disease and drug-induced mitochondrial dysfunction. It is reported here that ex vivo incubation with NV811 elicited an increase in platelet mitochondrial respiration in a paediatric patient with acute lymphoblastic leukaemia in remission.
References
Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, et al. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020;9:14.
Vrooman LM, Silverman LB. Treatment of Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Clinical Advances. Current Hematologic Malignancy Reports. 2016;11(5):385-94.
Kato M, Manabe A. Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatr Int. 2018;60(1):4-12.
Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM, Sinclair DA. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol 2022;18(4):243-58.
Diaz-Vegas A, Sanchez-Aguilera P, Krycer JR, Morales PE, Monsalves-Alvarez M, Cifuentes M, et al. Is Mitochondrial
Dysfunction a Common Root of Noncommunicable Chronic Diseases? Endocr Rev. 2020;41(3).
Sjövall F, Ehinger JKH, Marelsson SE, Morota S, Åsander Frostner E, Uchino H, et al. Mitochondrial respiration in human viable platelets—Methodology and influence of gender, age and storage. Mitochondrion. 2013;13(1):7-14.
Petrus AT, Lighezan DL, Danila MD, Duicu OM, Sturza A, Muntean DM, et al. Assessment of platelet respiration
as emerging biomarker of disease. Physiol Res 2019;68(3):347-63.
Kramer PA, Ravi S, Chacko B, Johnson MS, Darley-Usmar VM. A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: implications for their use as bioenergetic biomarkers. Redox Biol. 2014;2:206-10.
Baaten CCFMJ, Moenen FCJI, Henskens YMC, Swieringa F, Wetzels RJH, van Oerle R, et al. Impaired mitochondrial activity explains platelet dysfunction in thrombocytopenic cancer patients undergoing chemotherapy. Haematologica. 2018;103(9):1557-67.
Avram VF, Bîna AM, Sima A, Aburel OM, Sturza A, Burlacu O, et al. Improvement of Platelet Respiration by Cell Permeable Succinate in Diabetic Patients Treated with Statins. Life. 2021;11(4).
Piel S, Chamkha I, Dehlin AK, Ehinger JK, Sjövall F, Elmér E, et al. Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose. PLoS One. 2020;15(4):e0231173-e.
Bețiu AM, Chamkha I, Gustafsson E, Meijer E, Avram VF, Åsander Frostner E, et al. Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity. Int J Mol Sci. 2021;22(21):11786.
ALL IC BFM 2009 - A Randomized Trial of the I BFM-SG for the Management of Childhood non-B Acute Lymphoblastic Leukemia 2009. Available from: https://www.bialaczka.org/wp-content/uploads/2016/10/ ALLIC_BFM_2009.pdf.
Lelcu T, Bînă AM, Dănilă MD, Popoiu CM, Aburel OM, Arghirescu ST, et al. Assessment of Platelet Mitochondrial Respiration in a Pediatric Population: A Pilot Study in Healthy Children and Children with Acute Lymphoblastic Leukemia. Children. 2021;8(12).
Gnaiger Erich AFEN, A.K.; Abdel-Rahman, E.A.; Abumrad Nada, A.; Acuna-Castroviejo, D.; Adiele Reginald, C; Ahn BAM, B.; Ali Sameh, S.; Almeidam, A.; et al. . Mitochondrial physiology. Bioenerg Commun. 2020:1,44.
Gorini S, De Angelis A, Berrino L, Malara N, Rosano G, Ferraro E. Chemotherapeutic Drugs and Mitochondrial
Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib. Oxid Med Cell Longev. 2018;2018:7582730-.
Wang H, Fang B, Peng B, Wang L, Xue Y, Bai H, et al. Recent Advances in Chemical Biology of Mitochondria Targeting. Front Chem. 2021;9:683220.
Murphy MP, Hartley RC. Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov. 2018;17(12):865-86.
Ashton TM, McKenna WG, Kunz-Schughart LA, Higgins GS. Oxidative Phosphorylation as an Emerging Target in Cancer Therapy. Clin Cancer Res. 2018;24(11):2482-90.
de Beauchamp L, Himonas E, Helgason GV. Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia. Leukemia. 2022;36(1):1-12.
Ehinger JK, Piel S, Ford R, Karlsson M, Sjövall F, Frostner EÅ, et al. Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency. Nature Communications. 2016;7(1):12317.
Piel S, Ehinger JK, Chamkha I, Frostner EÅ, Sjövall F, Elmér E, et al. Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production. Intensive Care Med Exp. 2018;6(1):22-.
Avram VF, Chamkha I, Åsander-Frostner E, Ehinger JK, Timar RZ, Hansson MJ, et al. Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity. International journal of molecular sciences. 2021;22(1):424.
Owiredu S, Ranganathan A, Eckmann DM, Shofer FS, Hardy K, Lambert DS, et al. Ex vivo use of cell-permeable succinate prodrug attenuates mitochondrial dysfunction in blood cells obtained from carbon monoxide- poisoned individuals. Am J Physiol Cell Physiol. 2020;319(1):C129-C35.
Owiredu S, Ranganathan A, Greenwood JC, Piel S, Janowska JI, Eckmann DM, et al. In vitro comparison of hydroxocobalamin (B12a) and the mitochondrial directed therapy by a succinate prodrug in a cellular model of cyanide poisoning. Toxicol Rep. 2020;7:1263-71.
Bakare AB, Rao RR, Iyer S. Cell-Permeable Succinate Increases Mitochondrial Membrane Potential and Glycolysis in Leigh Syndrome Patient Fibroblasts. Cells. 2021;10(9):2255.
Janowska JI, Piel S, Saliba N, Kim CD, Jang DH, Karlsson M, et al. Mitochondrial respiratory chain
complex I dysfunction induced by N-methyl carbamate ex vivo can be alleviated with a cell-permeable succinate prodrug. Toxicol In Vitro. 2020;65:104794-.
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological reviews. 2014;94(3):909-50.
Liu B, Ezeogu L, Zellmer L, Yu B, Xu N, Joshua Liao D. Protecting the normal in order to better kill the cancer. Cancer Med. 2015;4(9):1394-403.
Fiorillo M, Ózsvári B, Sotgia F, Lisanti MP. High ATP Production Fuels Cancer Drug Resistance and Metastasis:
Implications for Mitochondrial ATP Depletion Therapy. Frontiers in Oncology. 2021;11.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).