What You Need To Know About The Role Of Lipotoxicity

Lipotoxicity, cellular senescence and mitochondrial dysfunction
Lipotoxicity - Mitochondrial disfunction - Senscence

Are you familiar with the term lipotoxicity ?

If so, I am sure you have come across it before. Today, let’s investigate the phenomenon a little more,
what are the links between lipotoxicity, cellular senescence and mitochondrial dysfunction?

Lipotoxicity, a metabolic syndrome resulting from lipid accumulation in the cell, is known to be one of the causes of mitochondrial dysfunction. It also accelerates the degenerative process of cellular senescence and subsequent carcinogenesis. Here, we would like to introduce some recent studies on this topic.

First of all, how does lipotoxicity accelerate the degenerative process of cellular senescence?
Before delving into the matter, let’s look back at what cellular senescence is.

Cellular senescence

Cellular senescence describes a phenomenon that makes cells arrest in a state of irreversible growth.

Although it has long been thought to be preventing abnormal or DNA-damaged cells from proliferating and thus serves as a carcinogenesis prevention mechanism, it has also been discovered that senescent cells acquire SASPs (senescence-associated secretory phenotypes) and secrete factors that promote carcinogenesis in surrounding cells.

Cellular senescence is indeed a double-edged sword. It is triggered by multiple endogenous and exogenous stress factors and therefore several types of cellular senescence are identified, such as DNA damage-induced senescence, replicative senescence, oncogene-induced senescence, mitochondrial dysfunction-associated senescence, epigenetically induced senescence, paracrine senescence, wound healing and embryonic development related senescence and so on1.

Characteristics of senescent cell

Lipotoxicity and cellular senescence

Now let’s take a look at the relationship between lipotoxicity and cellular senescence.

Lipotoxicity is also known as one of the causes of cellular senescence. As recent studies show excess lipids are easily attacked by reactive oxygen species (ROS) and other lipotoxic effects on mitochondria ultimately leading to mitochondrial dysfunction and cellular senescence2. Huizhen, Z. et al., focused on Carnitine palmitoyltransferase 1C (CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids. This enzyme had been also known as a critical regulator of tumor senescence but it was not known if loss of CPT1C could induce cellular senescence via lipotoxicity.
Therefore, they conducted an LC/MS-based lipidomic analysis of PANC-1, MDA-MB-231, HCT-116, and A549 cancer cells after siRNA depletion of CPT1C with subsequent cellular lipotoxicity assays. As a result, the knockdown of CPT1C could induce lipotoxicity resulting in cancer cellular senescence. This finding suggests that inhibition of CPT1C in tumor cells may serve as a new therapeutic strategy2.

The above study is one interesting example that shows relationship between accumulation of lipids and cellular senescence. However, it also contributes to mitochondrial dysfunction.

Mitochondrial dysfunction

Senescence-related and mitochondrial dysfunction-related disease

Mitochondria have multiple important functions in cells. One of their main functions is known as a production of ATP, however, not only that, they contribute to regulation of cellular metabolism, control of cell-and cell-death.

In the review made by Na, L. et.al., it is mentioned that there are many studies to suggest that alterations in mitochondrial homeostatic mechanisms, metabolites, and ROS generation can activate cellular senescence3.

Additionally, in senescent cells, mitochondrial dynamics are considered to be strongly reduced. In the ultrastructural study, senescent cells are revealed to have defective enlarged mitochondria in the majority of cells with perturbed morphology of cristae4.

Observation of Internal Structure of Mitochondria by Super-resolution Laser Microscopy (STED) using Dojindo’s MitoBright LT Deep Red. *This data is obtained from Dr. Ikuroh Ohsawa and Dr. Yasunori Fukita at Tokyo Metropolitan Institute of Gerontology.

Not only mitochondria and their dysfunction are closely related to cellular senescence, it is also closely related to neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

Cellular senescence has been also regarded as a primary inducing factor of age-associated neurodegenerative disorders, and therefore, some studies had been focusing on targeting astrocyte senescence as a novel and feasible therapeutic approach for Alzheimer’s disease5. This suggests that the relationship between role and dysfunction of mitochondria, and cellular senescence, and then resulting disorders is not simply one-way but it is like an intricate jigsaw puzzle.

Another interesting study shows the relationship between lipid accumulation and mitochondrial dysfunction. The induction of apoptosis from DNA damage induced by etoposide leads to an early increase in cytoplasmic lipid droplet formation and mitochondrial membrane potential6. Therefore, mitochondrial membrane potential is widely studied as a promising target for lipotoxicity-related diseases.

Monitoring mitochondrial membrane potential by Dojindo’s MT-1 MitoMP Detection Kit

Moreover, several studies report that lipid droplets accumulate in senescent cells by DNA damage7. In other words, it has been shown that lipid droplets accumulation in cells causes cellular senescence.

Lipid droplet detection by Dojindo’s Lipi-dyes

Conclusion

Lipotoxicity resulting from lipid accumulation thus has a deep relationship with cellular senescence and mitochondrial dysfunction.

Are you interested in exploring and studying more about this topic ?

Contact your local Tebubio office to get more information about dedicated solutions we can offer you, and don’t hesitate to take a look at the Dojindo probes and kits portfolio on our website.

References

  1. Na, L. et al., “Aging and stress induced ß cell senescence and its implication in diabetes development”, Aging (Albany NY), 2019, 11(21), 9947–9959.
  2. Huizhen, Z. et al., “Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence”, Journal of Pharmaceutical Analysis, 2020.
  3. Clara, C. al., “Mitochondria: Are they causal players in cellular senescence?”, Biochimica et Biophysica Acta – Bioenergetics, 2015, 1847(11), 1373-1379.
  4. Vasileiou, P. et al., “Mitochondrial Homeostasis and Cellular Senescence”, Cells, 2019, 8(7), 686.
  5. Xiaojuan, H. et al., “Astrocyte Senescence and Alzheimer’s Disease: A Review”, Front. Aging Neurosci., 2020.
  6. Borén, J. et al., “Apoptosis-induced mitochondrial dysfunction causes cytoplasmic lipid droplet formation”, Cell Death Differ, 2012, 19(9), 1561-1570.
  7. Hamsanathan, S. et al., “Lipids as Regulators of Cellular Senescence”, Front. Physiol., 2022, 13, 796850.