Vol. 24, Issue 1: Fall 2016

Disease Prevention: The Unexpected Benefits of Lipids and Stress discovered in a New Cellular Response

Gianina Wicaksono

When referring to mitochondria, people immediately jump to its role as the powerhouse of the cell. Similarly, when discussing stress, people will frequently cite its fat-increasing function. However, few people will consider their dual-roles as the key to brain degeneration, and an unexpected life-saver, respectively. Dr. Andrew Dillin ‘s lab at the Stem Cell Research in UC Berkeley’s Department of Molecular and Cell Biology published their conclusions supporting this claim in the September, 2016 edition of Cell. The Howard Hughes Medical Institute investigator was aware that certain neurodegenerative illnesses are caused by plaques from abnormal proteins, and decided to investigate a seemingly unrelated cell organelle: the mitochondria. In the darkness, frustration, and mystery that surrounds neurodegenerative diseases such as Huntington’s, Parkinson’s and Alzheimer’s diseases , Dr. Dillin has renewed the hope for new cures through his research surrounding nematodes, while also suggesting that stress — specifically, fat-inducing stress — is beneficial.

Equilibrium is an important factor in the general well-being of all organisms. Efficient communication is also crucial in maintaining cells’ homeostasis. Miscommunication within organelles and cells can be the primary cause of a neurodegenerative disease, cardiovascular disease, and diabetes. Within cells, organelles are “compartmentalized” to facilitate the maintenance of equilibrium. This means that different parts of cells have their own special way of reacting to stress, especially in the endoplasmic reticulum, mitochondria, and cytoplasm. These are referred to as unfolded protein responses. Prior research has found that the chaperone hsp70 is responsible for the execution of these unfolded protein responses, transporting proteins, folding newly-formed proteins, and even refolding aggregated or misfolded proteins.

Dillin’s lab performed a series of experiments utilizing genetically engineered mitochondria to induce Huntington’s disease in nematode C. elegans to explore the functionality of hsp70 within different organelles and in relation to cell homeostasis. His experiments revealed that abnormally-folded proteins aggregate in the mitochondria, and that stress response is mediated by fat accumulation and synthesis, and is elicited by heat shock. This newly discovered stress response in the mitochondria (which has officially been termed as the Mitochondrial-to-Cytosolic Stress Response and is abbreviated as the MCSR) helps improve homeostasis in both the mitochondria and the cytosol.

Dillin explored hsp70 functionality in a MCSR response by testing if a gene-unfolding response in the mitochondria could communicate to other organelles and cells, and indeed, the cell lost homeostasis. This indicates that the mitochondria is in charge of intracellular and intercellular communication. Further experiments explored the circumstances in which MCSR is initiated. Dillin found that MCSR is induced when the knockdown of mitochondrial chaperone follows a heat shock response and the unfolding of the genes. Further analysis also shows that the necessary steps to induce the MCSR has a side effect of enriching genes that aid in lipid biosynthesis. When testing whether fat accumulation has any relationship with MCSR induction, Dillin’s lab discovered that reduced fat accumulation does hinder the start of MCSR, and that cardiolipin, a particular phospholipid found in the mitochondria , is crucial in the induction of the MCSR.Lastly, Dillin performed experiments that tested if his results translate into a mammalian system in order to verify if this phenomena is also found in humans. Dillin tested this via human primary fibroblast cells, and interestingly, the same response was seen in those cells, suggesting the phenomena happens in human cells as well.

Dr. Andrew Dillin has modeled the mechanism he has discovered within our cells, in which fat accumulation triggers the activation of the MCSR response, which further increases lipid production to promote homeostasis and prevent the misfolding of proteins. This control would then help prevent the organism from obtaining neurodegenerative diseases such as Huntington’s disease or Alzheimer’s. With this research in mind, medicines could be created that help induce hsp70, which in turn induces fat accumulation and ultimately starts the MCSR process to fix the misfolded proteins. When asked about future prospects of this discovery in a UC Berkeley interview, Dr. Dillin comments on a treatment prospect, particularly for his disease focus --Huntington’s disease: “If we could manipulate this lipid pathway, we could go after Huntington's disease, because in our studies the drugs were really beneficial.” Dr. Dillin comments further, “Maybe there is a way to use one drug to alter the mitochondrial signal and another drug to alter the communication signal from the brain.” Perhaps, fat and stress should not be vilified. Perhaps, a little bit of stress — and fat accumulation — may help humans live a little longer, after all.

About the Author

Gianina Wicaksono is a freshman at Cal from Ithaca, New York. She intends to double major in Molecular Environmental Biology and Economics, following the pre-med track. She is very passionate about music and loves reading materials related to interesting medical phenomena, particularly neuroscience. Her future goals include medical school and/or consulting.