Platelet-derived mitochondrial transplantation expands respiratory reserve and extracellular matrix anabolism in primary osteoarthritic chondrocytes.
18 affiliations
- 1Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, 7620001, Chile.
- 2Centro de Investigación Clínica Avanzada, Hospital Clínico Universidad de Chile, Santiago, 8380453, Chile.
- 3IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, 7620001, Chile.
- 4Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, 2340000, Chile.
- 5Escuela de Kinesiología, Facultad de Medicina, Universidad de Los Andes, Santiago, 7620001, Chile.
- 6Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Universidad del Desarrollo, Santiago, 7610315, Chile.
- 7Centro Ciencia y Vida, Fundación Ciencia y Vida, 8580704 , Santiago, Chile.
- 8Instituto de Ciencias Biomédicas, Facultad de Medicina y Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, 8370071, Chile.
- 9Centre for Organismal Studies (COS), Cytoskeleton, Cell division and Signaling Unit, University of Heidelberg, 69120, Heidelberg, Germany.
- 10IRMB, Univ Montpellier, INSERM, Montpellier, 34295, France.
- 11Departamento de Ortopedia y Traumatología, Hospital Clínico Universidad de Chile, Santiago, 8380453, Chile.
- 12Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, 7620001, Chile. [email protected].
- 13IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, 7620001, Chile. [email protected].
- 14Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, 7620001, Chile. [email protected].
- 15Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, 8380453, Chile. [email protected].
- 16Centro de Investigación Clínica Avanzada, Hospital Clínico Universidad de Chile, Santiago, 8380453, Chile. [email protected].
- 17Centro de Investigación Clínica Avanzada, Hospital Clínico Universidad de Chile, Santiago, 8380453, Chile. [email protected].
- 18Departamento de Ciencias de la Salud, Universidad de Aysén, Coyhaique, 5951537, Chile. [email protected].
Abstract
Background
Osteoarthritis (OA) is a leading cause of disability worldwide, driven by the complex interplay of aging, obesity, and mechanical stress, which converge on progressive deterioration of cartilage, subchondral bone, and synovial tissue. Current treatments alleviate symptoms but fail to halt the degenerative process, making joint replacement surgery the only definitive option for advanced disease. A central mechanism underlying OA pathogenesis is mitochondrial dysfunction in chondrocytes, in which the balance between oxidative phosphorylation (OXPHOS) and glycolysis is disrupted, leading to impaired OXPHOS, accumulation of reactive oxygen species (ROS), and sustained overproduction of matrix-degrading enzymes and pro-inflammatory cytokines. Mitochondrial transplantation has emerged as a promising strategy to restore cellular bioenergetics, and platelets, which contain functional, respiration-competent mitochondria, represent an accessible allogenic donor source.Methods
Mitochondria isolated from platelets of healthy donors were structurally and functionally characterized and transplanted into primary human OA chondrocytes by mitoception at increasing chondrocyte-to-mitochondria ratios. Internalization was assessed by flow cytometry and confocal colocalization analysis. Bioenergetic effects were quantified by Seahorse extracellular flux analysis; mitochondrial membrane potential and superoxide production were measured by flow cytometry; extracellular matrix protein expression was evaluated by immunofluorescence and RT-qPCR; and the inflammatory secretome was profiled by Luminex multiplex assay.Results
Isolated platelet mitochondria preserved outer membrane integrity, membrane potential, and ADP-coupled respiratory activity prior to transplantation. They were efficiently internalized by OA chondrocytes in a dose-dependent manner, with optimal uptake observed at chondrocyte-to-platelet-equivalent mitochondria dose ratios of 1:100. Transplantation increased maximal respiratory capacity and spare respiratory reserve without altering basal respiration, was accompanied by elevated type II collagen and aggrecan protein levels, and selectively reduced secreted IL-1β and osteopontin while leaving IL-6, TNF-α, IL-10, and IL-1RA unchanged. Mitochondrial superoxide production was modestly increased and was prevented by the mitochondria-targeted antioxidant MitoTEMPO, while mitochondrial membrane potential remained unchanged.Conclusions
Platelet-derived mitochondrial transplantation expands the respiratory reserve and modulates the catabolic-anabolic balance of human OA chondrocytes without inducing mitochondrial depolarization, providing a mechanistic basis for allogenic, blood-derived mitochondrial therapies in joint disease.
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BibTeX
@article{jeraldoaraya2026plateletderived,
title = {{Platelet-derived mitochondrial transplantation expands respiratory reserve and extracellular matrix anabolism in primary osteoarthritic chondrocytes.}},
author = {Nicole Jeraldo-Araya and Liliana Yantén-Fuentes and María Paz Hernández-Cáceres and Jonathan Morales-Reyes and Ana María Vega-Letter and Eliana Lara-Barba and Cesar Merino-Flores and Felipe A Bustamante-Barrientos and Iván Alfaro and Andrea Matamoros and Álvaro A Elorza and Camila García-Navarrete and Noymar Luque-Campos and Maximiliano Barahona and Claudia Altamirano and Patricia Luz-Crawford and Pablo Cruz and Jorge A Toledo},
journal = {Journal of translational medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08809-4},
url = {https://europepmc.org/article/MED/42958393},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Platelet-derived mitochondrial transplantation expands respiratory reserve and extracellular matrix anabolism in primary osteoarthritic chondrocytes.
AU - Nicole Jeraldo-Araya
AU - Liliana Yantén-Fuentes
AU - María Paz Hernández-Cáceres
AU - Jonathan Morales-Reyes
AU - Ana María Vega-Letter
AU - Eliana Lara-Barba
AU - Cesar Merino-Flores
AU - Felipe A Bustamante-Barrientos
AU - Iván Alfaro
AU - Andrea Matamoros
AU - Álvaro A Elorza
AU - Camila García-Navarrete
AU - Noymar Luque-Campos
AU - Maximiliano Barahona
AU - Claudia Altamirano
AU - Patricia Luz-Crawford
AU - Pablo Cruz
AU - Jorge A Toledo
PY - 2026
DA - 2026/08/20
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08809-4
UR - https://europepmc.org/article/MED/42958393
AB - Background Osteoarthritis (OA) is a leading cause of disability worldwide, driven by the complex interplay of aging, obesity, and mechanical stress, which converge on progressive deterioration of cartilage, subchondral bone, and synovial tissue. Current treatments alleviate symptoms but fail to halt the degenerative process, making joint replacement surgery the only definitive option for advanced disease. A central mechanism underlying OA pathogenesis is mitochondrial dysfunction in chondrocytes, in which the balance between oxidative phosphorylation (OXPHOS) and glycolysis is disrupted, leading to impaired OXPHOS, accumulation of reactive oxygen species (ROS), and sustained overproduction of matrix-degrading enzymes and pro-inflammatory cytokines. Mitochondrial transplantation has emerged as a promising strategy to restore cellular bioenergetics, and platelets, which contain functional, respiration-competent mitochondria, represent an accessible allogenic donor source.Methods Mitochondria isolated from platelets of healthy donors were structurally and functionally characterized and transplanted into primary human OA chondrocytes by mitoception at increasing chondrocyte-to-mitochondria ratios. Internalization was assessed by flow cytometry and confocal colocalization analysis. Bioenergetic effects were quantified by Seahorse extracellular flux analysis; mitochondrial membrane potential and superoxide production were measured by flow cytometry; extracellular matrix protein expression was evaluated by immunofluorescence and RT-qPCR; and the inflammatory secretome was profiled by Luminex multiplex assay.Results Isolated platelet mitochondria preserved outer membrane integrity, membrane potential, and ADP-coupled respiratory activity prior to transplantation. They were efficiently internalized by OA chondrocytes in a dose-dependent manner, with optimal uptake observed at chondrocyte-to-platelet-equivalent mitochondria dose ratios of 1:100. Transplantation increased maximal respiratory capacity and spare respiratory reserve without altering basal respiration, was accompanied by elevated type II collagen and aggrecan protein levels, and selectively reduced secreted IL-1β and osteopontin while leaving IL-6, TNF-α, IL-10, and IL-1RA unchanged. Mitochondrial superoxide production was modestly increased and was prevented by the mitochondria-targeted antioxidant MitoTEMPO, while mitochondrial membrane potential remained unchanged.Conclusions Platelet-derived mitochondrial transplantation expands the respiratory reserve and modulates the catabolic-anabolic balance of human OA chondrocytes without inducing mitochondrial depolarization, providing a mechanistic basis for allogenic, blood-derived mitochondrial therapies in joint disease.
SN - 1479-5876
ER -