Molecular and metabolic mechanisms underlying mitochondrial dysfunction

Research summary:

Mitochondria are unique and complex organelles that perform essential functions in many aspects of cell biology. Once considered to be mere sites of ATP generation, it is now evident that these organelles participate in a wide range of cellular processes including calcium homeostasis, apoptosis, redox balance or cell fate. Because of this multifaceted contribution of mitochondria to key biologic and metabolic pathways it is not surprising that mitochondrial dysfunction has been linked to many human disorders including neurodegeneration, diabetes, cancer or aging. The Balsa laboratory seeks to understand the basic molecular components that regulate mitochondrial function and integrate this knowledge in the context of human physiology and disease.

We are currently exploring two central areas. First, we aim to elucidate the molecular mechanisms whereby mitochondrial dysfunction compromise cellular fitness and leads to organ failure in the context of human diseases. Second, we focus on understanding how cancer cells adapt to unfavoured tumour microenvironments by rewiring their mitochondrial metabolism to enable tumour growth and survival.

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Fig.1: Model depicting how inhibition of PPP-generated NADPH is compensated in WT cells by enhancing mitochondrial one-carbon metabolism and induction of ALDH1L2. Cells with defects in complex I displayed reduction of serine catabolism and concomitant NADPH production, which reduced GSH levels and increased oxidative stress, inflammation, and cell death. ME1 overexpression is able to rescue redox imbalance by acting as a potent source of NADPH and represents a potential therapeutic target to treat disorders associated with ETC dysfunction.

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Fig. 2: Glucose deprivation leads to an increase in mitochondrial ATP generation. During glucose-deprivation, PERK is activated, stimulating increases in mitochondrial cristae density. In parallel, the PERK-eIF2a-ATF4 axis transcriptionally increases SCAF1 levels to assist in the formation of CIII- and CIV-containing supercomplexes. Overall, these molecular changes aim to stimulate the OXPHOS system and increase ATP production when crucial nutrients such glucose are scarce.

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Last nameNameLaboratoryExt.*e-mailProfessional category
Balsa MartínezEduardo4401ebalsa(at)cbm.csic.esInvestigador

Relevant publications:

  • Balsa E, Perry EA, Bennett CF, Jedrychowski M, Gygi SP, Doench J, Puigserver P. Defective NADPH Production in Mitochondrial Disease Complex I Causes Inflammation and Cell Death. Nature Communications. 2020.
  • Luo C, Balsa E, Perry EA, Liang J, Tavares CD, Vazquez F, Widlund HR, Puigserver P. H3K27me3-mediated PGC1α gene silencing promotes melanoma invasion through WNT5A and YAP. J Clin Invest. 2020 Jan 13. pii: 130038.
  • Balsa E, Soustek MS, Thomas A, Cogliati S, Garcia-Poyatos C, Martin-Garcia E, Jedrychowski M, Gygi SP, Enríquez JA, Puigserver P. ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes Through PERK/eIF2α Axis. Mol Cell. 2019. Jun 6;74(5):877-890.
  • Soustek MS, Balsa E, Barrow JJ, Jedrychowski M, Vogel R, Jan Smeitink, Gygi SP, Puigserver P. Inhibition of the ER stress IRE1α inflammatory pathway protects against cell death in mitochondrial complex I mutant cells. Cell Death Dis. 2018 May 31;9(6):658.
  • Luo C, Balsa E, Thomas A, Hatting M, Jedrychowski M, Gygi SP, Widlund HR, Puigserver P. ERRα Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1α-Elevated Melanomas. Mol Cancer Res. 2017 Oct;15(10):1366-1375
  • Barrow JJ*, Balsa E*, Verdeguer F, Tavares CDJ, Soustek MS, Hollingsworth IV LR, Jedrychowski M, Vogel R, Paulo J, Smeitink J, Gygi S, Doench J, Root D, Puigserver P. Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations. Mol Cell 2016. Oct 6; 64(1): 163-175. (*Co-first author).
  • Soro-Arnaiz I, Li QOY, Torres-Capelli M, Meléndez-Rodríguez F, Veiga S, Veys K, Sebastian D, Elorza A, Tello D, Hernansanz-Agustín P, Cogliati S, Moreno-Navarrete JM, Balsa E, Fuertes E, Romanos E, Martínez-Ruiz A, Enriquez JA, Fernandez-Real JM, Zorzano A, De Bock K, Aragonés J. Role of Mitochondrial Complex IV in Age-Dependent Obesity. Cell Rep. 2016 Sep 13;16(11):2991-3002.
  • Lapuente-Brun E, Moreno-Loshuertos R, Acín-Pérez R, Latorre-Pellicer A, Colás C, Balsa E, Perales-Clemente E, Quirós PM, Calvo E, Rodríguez-Hernández MA, Navas P, Cruz R, Carracedo Á, López-Otín C, Pérez-Martos A, Fernández-Silva P, Fernández-Vizarra E, Enríquez JA. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science. 2013 Jun 28;340(6140):1567-70
  • Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA. NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metab. 2012 Sep 5;16(3):378-86
  • Tello D*, Balsa E*, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez Á, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity. Cell Metab. 2011 Dec 7;14(6):768-79. (*Co-first author).

Funding:

  • Ministerio de Ciencia e Innovación (MICINN):
    • Ramón y Cajal 2018 (RYC2018-024342-I)
    • Programa Estatal de I+D+i (PID2019-110766GA-I00)

  • EC-European Research Council:
    • ERC Starting Grant (2020 ERC-Stg) 948478 MitoCure

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