TANGO2 plays a role in lipid metabolism and affects cellular organization during starvation.
About the author
Olga (Olya) Vvedenskaya
Sci. Communications Officer
Dr. Dr. Olya Vvedenskaya studied medicine, and further obtained her PhD in the field of molecular oncology. She loves to deliver scientific messages in a clear and accessible manner.
• TANGO2 protein localizes in mitochondria and close to ER
• Cells with depleted TANGO2 have larger lipid droplets
• TANGO2 depletion changes the lipidome response to starvation
Olga (Olya) Vvedenskaya
Sci. Communications Officer
Dr. Dr. Olya Vvedenskaya studied medicine, and further obtained her PhD in the field of molecular oncology. She loves to deliver scientific messages in a clear and accessible manner.
TANGO2, a crucial protein encoded by the TANGO2 gene in humans, plays a key role in important cell activities like ER-to-Golgi transport and maintaining the health of mitochondria. While it is known that TANGO2 is vital in these cell functionalities, the specific details of its functions are not completely clear. When mutations occur in the TANGO2 gene, it disrupts mitochondrial processes, increases stress in the endoplasmic reticulum, and decreases the density of Golgi structures.
These mutations lead to early symptoms like low blood sugar, high ammonia levels, muscle breakdown, heart rhythm issues, and brain disorders. Over time, these initial symptoms can progress to cognitive problems, showcasing the significant impact of TANGO2 mutations on cell functions. Understanding how TANGO2 interacts with cell processes provides valuable insights into the reasons behind these severe health problems.
Agustin Leonardo Lujan and their colleagues observed a significant co-localization of the TANGO2 marker and the marker for mitochondria. TANGO2 was found to be concentrated at locations where mitochondria are closely positioned to the endoplasmic reticulum (ER) and lipid droplets (LDs). Specifically, TANGO2 primarily associates with the outer membrane of mitochondria, especially at sites where mitochondria are in close proximity to both the ER and LDs.
TANGO2 is frequently present at locations identified by lipid droplets. This observation led the authors to investigate the impact of TANGO2 depletion on lipid metabolism and LDs within normal cells and cells undergoing starvation. The results indicate that the absence of TANGO2 significantly enlarges LDs, attributed to a combination of increased biogenesis and a notable impairment in the process of lipolysis.
The alteration in lipid droplet size in cells lacking TANGO2 motivated the researchers to examine shifts in the overall cellular lipid composition under normal conditions and during starvation.
Changes in lipidomics of starved TANGO2-depleted cells. Relative changes in lipid classes under various conditions: nutrient starvation (left), cells with depleted TANGO2 under normal conditions (middle), and cells with depleted TANGO2 during nutrient starvation (right).
Agustin Leonardo Lujan et al., eLife 2023, 12:e85345.; 10.7554/eLife.85345
Further detailed analysis of lipidomes showed elevated levels of lysophosphatidic acid (LPA) and reduced levels of phosphatidic acid (PA) in TANGO2-deficient cells, with the change of these lipid profiles during starvation. Moreover, there was a substantial decrease in cardiolipin (CL) levels, typically derived from PA in these cells.
Additionally, the authors noticed that the absence of TANGO2 influences the levels of enzymes engaged in both phospholipid and neutral lipid metabolism. Further, TANGO2 depletion induces unsaturated lipid peroxidation, a known factor in the modification of lipid quality.
Selected lipid classes in TANGO2-depleted cells under starvation. Lipid classes (A – lysophosphatidic acid (LPA), B – phosphatidic acid (PA), C – cardiolipin (CL)). **, P ≤ 0.01; ***, P ≤ 0.001.
Agustin Leonardo Lujan et al., eLife 2023, 12:e85345.; 10.7554/eLife.85345
Overall, the authors observed that TANGO2 primarily localizes to mitochondria in mammalian cells, with a partial presence at regions where the ER and LDs come into close contact with mitochondria. When TANGO2 was knocked down, there was a noticeable increase in LD size and a rise in intracellular reactive oxygen species levels. Additionally, these changes were more pronounced when cells were cultured in low-nutrient media causing starvation. Importantly, these cellular characteristics align with those observed in cells from individuals with TANGO2 mutations.
These findings suggest that TANGO2 plays a role in lipid homeostasis, particularly in acyl-CoA metabolism. Moreover, they propose that defects in lipid metabolism, exacerbated under conditions of nutrient starvation, are the primary culprits behind starvation-induced acute rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias associated with TANGO2 mutations.
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The Centre for Genomic Regulation (CRG) is an international biomedical research institute. Its interdisciplinary teams focus on understanding life from the genome to a whole organism and its interaction with the environment, offering an integrated view of genetic diseases.
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