2024-03-28T10:55:59Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1335492021-12-27T15:42:54Zcom_10261_79com_10261_1col_10261_332
DIGITAL.CSIC
author
Marín-Buera, Lorena
author
López-Bernardo, Elia
author
Cadenas, Susana
author
Ugalde, Cristina
funder
Instituto de Salud Carlos III
funder
Comunidad de Madrid
2016-06-16T08:09:47Z
2016-06-16T08:09:47Z
2015-01-15
Journal of Proteomics 113: 38- 56 (2015)
http://hdl.handle.net/10261/133549
10.1016/j.jprot.2014.09.007
http://dx.doi.org/10.13039/501100004587http://dx.doi.org/10.13039/100012818
25239759
© 2014 Elsevier B.V. We have analyzed the cellular pathways and metabolic adaptations that take place in primary skin fibroblasts from patients with mutations in BCS1L, a major genetic cause of mitochondrial complex III enzyme deficiency. Mutant fibroblasts exhibited low oxygen consumption rates and intracellular ATP levels, indicating that the main altered molecular event probably is a limited respiration-coupled ATP production through the OXPHOS system. Two-dimensional DIGE and MALDI-TOF/TOF mass spectrometry analyses unambiguously identified 39 proteins whose expression was significantly altered in complex III-deficient fibroblasts. Extensive statistical and cluster analyses revealed a protein profile characteristic for the BCS1L mutant fibroblasts that included alterations in energy metabolism, cell signaling and gene expression regulation, cytoskeleton formation and maintenance, and intracellular stress responses. The physiological validation of the predicted functional adaptations of human cultured fibroblasts to complex III deficiency confirmed the up-regulation of glycolytic enzyme activities and the accumulation of branched-chain among other amino acids, suggesting the activation of anaerobic glycolysis and cellular catabolic states, in particular protein catabolism, together with autophagy as adaptive responses to mitochondrial respiratory chain dysfunction and ATP deficiency. Our data point to an overall metabolic and genetic reprogramming that could contribute to explain the clinical manifestations of complex III deficiency in patients. Biological significance: Despite considerable knowledge about their genetic origins, the pathophysiological mechanisms that contribute to the clinical manifestations of mitochondrial disorders remain poorly understood. We have investigated the molecular pathways and metabolic adaptations that take place in primary skin fibroblasts from patients with mutations in the BCS1L gene, a primary cause of mitochondrial complex III enzyme deficiency. Two-dimensional DIGE together with MALDI-TOF/TOF mass spectrometry and physiological validation analyses revealed a significant metabolic and genetic reprogramming as an adaptive response to mitochondrial respiratory chain dysfunction. Our data provide information about specific protein targets that regulate the transmitochondrial functional responses to complex III deficiency, thereby opening new doors for future research.
eng
openAccess
BCS1L
Complex III deficiency
2D-DIGE
Mitochondria
OXPHOS system
Respiratory chain
Differential proteomic profiling unveils new molecular mechanisms associated with mitochondrial complex III deficiency
artículo
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URL
https://digital.csic.es/bitstream/10261/133549/1/L%c3%b3pez%20Bernado%20Elia%20Differential%20proteomic.pdf
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López Bernado Elia Differential proteomic.pdf
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López Bernado Elia Differential proteomic.pdf.txt