Mitochondrial dynamics and physiology of intercellular transfer in the nervous system and gliomas

Molecular and Cellular Neurobiology
Instituto Cajal CSIC

Determinants of mitochondrial physiology and intercellular transfer in the nervous system.

Our work aims to unravel the molecular mechanisms that drive a wide variety of neurological disorders, especially those characterized by neurodegeneration and cancer, that are underscored by an altered mitochondrial function. To this end, we address the interplay between mitochondrial morphology, ultrastructure, and dynamics in the regulation of neural metabolism, respiration, redox status and bioenergetics. We focus our main interest on addressing the coordination of mitochondrial function between cells and tissues. In special, we tackle the transfer and acquisition of mitochondrial content, either as whole organelles or particles of mitochondrial origin. To characterize the molecular actors that govern these processes and a mitochondrial morphofunctional reconfiguration, we address three main areas:

i) Mitochondrial dynamics, metabolism and bioenergetics: We follow the dynamic changes in mitochondrial morphology, ultrastructure, transport and functionality. Dissecting the molecular players that govern these processes is key to modulate them at providing a therapeutic benefit in neurological diseases.

ii) Intercellular communication and mitochondrial exchange: Intercellular mitochondrial communication and traffic, particularly through tunneling nanotubes or tumor microtubes, has shown to be key in determining a proper function of the nervous system. We address these processes at the molecular level, as well as the acquisition of mitochondria as free organelles or included in microvesicles. Our objective is to describe the mechanisms by which mitochondria and intercellular communication drive neurodegeneration or oncogenesis in the nervous system.

iii) Mitochondrial transfer and morphofunctional reconfiguration: Intercellular transfer allows healthy mitochondria to integrate neighbor cells. Likewise, the transmission of damaged organelles for surrogate degradation or mitophagy is equally possible. Addressing how both forms of transfer reconfigure metabolism and bioenergetics, to define the physio(path)ology of the nervous system, represents for us a key objective to explore unprecedented therapeutic approaches in neurological disorders.

In brief, we aim to:

  • Adress a morphofunctional characterization of intercellular communication processes and mitochondrial transfer.
  • Identify molecular determinants of neural import, integration and reprogramming.
  • Study the impact of intercellular mitochondrial transfer on the bioenergetic, metabolic, respiratory and oxidative remodeling of neural cells.
  • Provide novel therapeutic applications based on the modulation of these processes in neurodegeneration and oncology.

Rubén Quintana-Cabrera (Ramón y Cajal Fellow, appointed Científico Titular CSIC).

Awards to Master works (TFMs) directed by the Principal Investigator:

  1. 11/2019    XVIII Archimedes University Contest Award. Ministry of Science, Innovation and Universities. Madrid, November 29, 2019.
  2. 07/2019   Poster award. 42nd Congress of the Spanish Society of Biochemistry and Molecular Biology. Madrid, 16-19 July 2019 (Spain)

Selected publications:

  • Quintana-Cabrera R* & Scorrano, L. (*co-corresponding). 2023. Determinants and outcomes of mitochondrial dynamics. Molecular Cell.
  • Lopez-Fabuel I, García-Macía M. et al. 2022. Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis. Nature Communications
  • Quintana-Cabrera R* et al. (*co-corresponding). 2021. Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria. Redox Biology.
  • Quintana-Cabrera R & Soriano ME. 2019. ER Stress Priming of Mitochondrial Respiratory suPERKomplex Assembly. Trends in Endocrinology & Metabolism.
  • Quintana-Cabrera R et al. 2018. The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function.  Nature Communications.
  • Cogliati S; et al. (5/15). 2013. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 155, pp.160-171.
  • Quintana-Cabrera R. et al.  2012. γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nature Communications. 3, pp.718.
Biomolecules & Cell D.
Molecular Biomedicine
Rubén Quintana-Cabrera