Research

Cancer metabolism

Mechanisms that regulate cell metabolism are a fundamental requirement for cell viability. Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes. In tumor cells, it has historically been assumed that mitochondrial metabolism is significantly diminished, while aerobic glycolysis is enhanced so that it becomes the major ATP source to fuel cancer cell proliferation, a phenomenon known as the Warburg effect. Nevertheless, recent studies have shown that the mitochondrial tricarboxylic acid (TCA) cycle is both functional and essential for tumor growth, because it provides cells with building blocks for the synthesis of macromolecules (proteins, lipids and nucleotides), and reducing equivalents which regulate the redox state of the cell. Therefore, we focus our research on understanding how mitochondrial activity is regulated and how we can modulate it in cancer cells.

We discovered that Ca²⁺ transfer from the endoplasmic reticulum (ER) to mitochondria, mediated through the inositol trisphosphate receptor channel (InsP3R), maintains normal mitochondrial activity and the absence of this signal generates a bioenergetic crisis that induces selective cancer cell death. We demonstrate that Ca²⁺ transfer to mitochondria is essential to maintain the activity of pyruvate, α-ketoglutarate and isocitrate dehydrogenases, key rate limiting enzymes of the TCA cycle. In this scenario, we hypothesize that in the absence of Ca²⁺, tumor cells are unable to use glutamine and the TCA cycle to generate the building blocks needed to proliferate and maintain homeostasis.

We expect that a deeper understanding of the regulation of mitochondria bioenergetics by InsP₃R-released Ca²⁺ will result in the identification of new therapeutic targets.

Mitochondrial function in Dysferlinophathies

The dysferlinopathies include different muscular dystrophy phenotypes; all of which are autosomal recessive, and are a consequence of mutations in the dysferlin gene (DYSF). Miyoshi’s distal myopathy (MM) and limb girdle muscular dystrophy 2B (LGMD2B), are the two more common dysferlinopathy phenotypes, and correspond to allelic disorders. The functionality of dysferlin in muscle cells is under active investigation. Pathogenesis of dysferlinopathy is attributed to impaired calcium-mediated muscle-membrane repair after normal stress injury. Abnormal mitochondria have been observed in myophaties like Pompe and Danon’s disease. Accumulation of damaged mitochondria usually reflects an autophagy malfunction, which generates a bioenergetic crisis sensed by AMPK, the master energy regulator of the cell. In the presence of dysferlinopathies, it is unknown whether mitochondria are functional and the bioenergetics state of cells is not understood. Thus, we aim to explore the signaling pathway that regulates cellular bioenergetics in this pathophysiological context and determine its potential as a therapeutic target.

Cellular senescence 

By 2050, close to one fifth of the Chilean population will be over 60 years old, making Chile one of the countries with the highest number of elderly people. Aging is one of the main risk factors for cancer, heart and neurodegenerative diseases. Cellular senescence, an irreversible cell cycle arrest, plays a big role in the decline of the regenerative potential and function of tissues, inflammation, and tumorigenesis in aged organisms. Thus, the identification, characterization, and pharmacological elimination of senescent cells have gained attention in the field of aging. As cellular senescence is accompanied by a change in metabolism and Ca²⁺ homeostasis, we aim to understand the role of mitochondria in the generation and maintenance of senescent cells and determine if the modulation of it activity can be used as a therapeutic tool.

Mitochondrial calcium in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder and the most frequent cause of dementia, affecting millions of people worldwide. . It is characterized clinically by major features such as a decline of intellectual and cognitive functions and irreversible memory loss. . Altered Ca²⁺ signaling and mitochondrial dysfunction are observed early in the development of the disease, long before the onset of measurable histopathology or cognitive deficits. However, the involvement of exaggerated Ca²⁺ signaling on mitochondrial dysfunction remains poorly understood. A molecular mechanism underlying exaggerated Ca²⁺ signaling is mediated in part by Ca²⁺ release from the endoplasmic reticulum (ER) through inositol 1,4,5-trisphosphate receptors (InsP3R). InsP3R are in close proximity with the mitochondrial Ca²⁺ uniporter (MCU), the ion channel responsible for sequestering Ca²⁺ into the mitochondrial matrix. We aim to study the relation InsP3R-MCU in an AD context and determine whether the normalization of Ca²⁺ signaling by decreasing IP3R activity will restore or prevent mitochondrial crisis and synaptic dysfunction in AD models.