top of page

RESEARCH

Aging_mitochondria.png

I have developed a keen interest in studying and understanding mitochondria biology in both health and disease states. Mitochondria are crucial organelles within cells, responsible for energy production in the form of adenosine triphosphate (ATP). Dysfunction of mitochondria is a hallmark of many neurodegenerative diseases, including Alzheimer's disease. The primary objective of my research is to gain a deeper understanding of mitochondrial function as well as disease-related mitochondrial impairments, with the aim of characterizing the biological basis for therapeutic interventions.

ER-mito SIM 1.jpg
Image website 2.jpg
wtTau GFP.jpg

Insight into our research focus

Mitochondrial dysfunction in tauopathy

The Tau protein belongs to the family of microtubule-associated proteins (MAPs), which stabilize microtubule assembly and function. Tau is present and plays vital roles in the brains of healthy individuals. It is expressed in most neurons and has been shown to participate in axonal transport, cell polarity, and neurotransmission.

Abnormal accumulation of tau is a significant characteristic observed in Alzheimer’s disease, frontotemporal lobar degeneration, Pick’s disease, and over 20 other serious neurodegenerative diseases. Despite its unclear physiological function, tau dysfunction consistently manifests in several neurodegenerative diseases, suggesting that understanding tau may lead to more effective treatments for patients afflicted by these conditions.

While substantial evidence has linked abnormal tau to neurodegeneration, the mechanisms underlying tau-induced neuronal dysfunction and death remain incompletely understood. Remarkably, abnormal tau protein has been demonstrated to impair mitochondrial bioenergetics and dynamics, thereby contributing to neurotoxicity.

Figure3_ impact of tau on mitochondria.tif

Therefore, the aim of our research is to dig deeper into the pathomechanisms of abnormal tau-induced mitochondrial failure. Our findings may help to identify new targets for therapeutic interventions.

Namely, we are currently studying the impact of abnormal tau on the coupling between the endoplasmic reticulum  and mitochondria.  This coupling coordinate and modulate many cellular functions, including mitochondrial cholesterol uptake and steroidogenesis. Defects in these processes may lead to neuronal dysfunction and death. 

Example of techniques used in this research axis:

Main models:

  • SH-SY5Y neuroblastoma cells stably expressing mutant tau versus control cells

  • Human induced pluripotent stem cells (hiPSCs) expressing tau mutations versus isogenic control cells

Main techniques:

  • Proximity ligation assay

  • Bioenergetic phenotyping (Seahorse XF Analyzer, Agilent)

  • Immunostaining and fluorescence microscopy

  • Real-time quantitative PCR, Western blots

  • Metabolomics

Intercellular mitochondria transfer

Intercellular mitochondria transfer is a form of cell signalling, in which whole mitochondria are transferred between cells in order to enhance cellular functions or aid in the degradation of dysfunctional mitochondria. Recent studies have highlighted intercellular mitochondria transfer between glial cells and neurons in the brain. Mitochondrial transfer has emerged as a key neuroprotective mechanism in a range of neurological conditions.

Figure 1.tif

However, the exact mechanisms that govern mitochondria transfer between brain cells are still unknown.

Therefore, we aim to answer the following questions:

  • how and in which condition intercellular mitochondria transfer occur between neurons and glial cells (here, astrocytes) ?

  • what happens in pathological conditions (e.g. in the presence of abnormal tau protein ?

  • Is it possible to artificially transplant functional exogenous mitochondria into disease cells for recovery or prevention of bioenergetic impairments ?

 

​

Example of techniques used in this research axis:

Main models:

  • SH-SY5Y neuroblastoma cells stably expressing mutant tau versus control cells

  • A172 glioma cells

  • Human induced pluripotent stem cells (hiPSCs) expressing tau mutations versus isogenic control cells

Main techniques:

  • Co-cultures (direct and indirect) of neurons and astrocytes

  • Immunostaining and fluorescence microscopy

  • Flow cytometry

  • Bioenergetic phenotyping (Seahorse XF Analyzer, Agilent), mitochondrial respiration (Resipher, Lucid Scientific)

  • Optogenetics (Mito-Killer Red)

Therapeutic approach against neurodegeneration

Growing evidence show that approaches preserving, improving, or rescuing brain bioenergetics would be promising therapeutic strategies against age-related neurodegenerative disorders (Cunnane S. C. et al., 2020).

Mito_E2.tif

The brain is the most energy-consuming organ of the body. Impairments in brain energy metabolism will affect neuronal functionality and viability. Mitochondria are the organelles which generate energy in cells.  Hence, mitochondrial dysfunction will ultimately lead to cellular impairments, ranging from subtle alterations in neuronal function to neurodegeneration.

Therefore, we aim to test the ability of different drugs / substances in improving mitochondrial function. Namely, we test the effects of:

  • plant-derived natural compounds

  • sex steroid hormones

​

Example of techniques used in this research axis:

Main models:

  • SH-SY5Y neuroblastoma cells (control cells, as well as cells expressing Alzheimer's disease-related proteins: tau or amyloid precursor protein)

  • Human induced pluripotent stem cells (hiPSCs)

Main readouts:

  • Cell viability / metabolic activity (MTT assay)

  • Mitochondrial metabolic activity (e.g. ATP production, mitochondria membrane potential)

  • Reduction / oxidation state (e.g. reactive oxygen species levels, NAD+/NADH ratio)

  • Bioenergetic phenotyping (Seahorse XF Analyzer, Agilent), mitochondrial respiration (Resipher, Lucid Scientific)

  • Mitochondrial morphology (immunostaining, fluorescence microscopy)

  • Mitophagy

bottom of page