Aging, and the mechanics behind it, remains one of the most closely guarded secrets of life.
As we age, our cells begin to show signs of stress, and specific pathways are activated to recycle and repair their machinery.
A team of investigators at the Medical University of South Carolina (MUSC) has recently characterized a novel player in these pathways, a protein that they have dubbed P17/PERMIT.
The team was led by Besim Ogretmen, Ph.D., SmartState Endowed Chair in Lipidomics and Drug Discovery at MUSC and co-leader of the Developmental Cancer Therapeutics Research Program at Hollings Cancer Center. The team reports its findings in the September 2019 issue of Science Advances.
This finding could provide critical insights into age-related diseases such as cancer and Alzheimer's, conditions in which mitochondrial function is aberrant.
Mitochondria function as the engines of our bodies, using the oxygen we breathe to burn the fuel we consume. As mitochondria age, they become prone to leaking the energy they work to generate. This energy supercharges the oxygen in our cells, leading to highly reactive radical oxygens, which our body attempts to purge with antioxidants.
Leaky mitochondria are bad news for the cell. So ceramide, a molecule that is produced in response to cell stress and damage, sends a signal to trigger digestion of the old mitochondria. This process is known as "mitophagy." When there's too much damage for the cell to repair normally, ceramide can instead signal the cells to undergo a form of controlled cell death.
What makes PERMIT exciting is the role it serves in the beginning steps of mitochondrial regulation. In response to stress, the cell begins to make the enzyme responsible for producing ceramide. PERMIT associates with the newly made enzyme and drags it to the mitochondria. The enzyme, known as CerS1, can then mass-produce ceramide at the precise location needed for mitochondrial regulation.
"It's very exciting that we were able to discover and characterize PERMIT," said Natalia Oleinik, Ph.D., the scientist on Ogretmen's team responsible for discovering CerS1. "By inducing cell stress and monitoring the various proteins that bind CerS1, we were able to show that PERMIT was the protein responsible for bringing CerS1 to the mitochondria."
By understanding how the cell responds to stress, and how the proteins that control stress are used, the MUSC team is another step closer to understanding debilitating conditions that result from the buildup of defective mitochondria.
Cancer cells can become reliant on defective mitochondria to fuel their growth and progression, ignoring the normal signals that would force them to self-destruct.
Meanwhile, the misfolded proteins that accumulate and contribute to Alzheimer's pathology may have their start with improper clearance of damaged mitochondria.
In unravelling the secrets of mitochondrial maintenance, the team at MUSC hopes to one day develop a therapeutic that would mimic the signals the ceramides provide, allowing proper clearance of the damaged mitochondria.
"We're trying to understand the connection between cancer and Alzheimer's, and this protein might be the link," said Ogretmen in regard to PERMIT. "Our idea here is that, without changing PERMIT, we can generate ceramides in the mitochondria with targeted therapeutics. That would be best for both diseases, as it would help treat cancers and help resolve issues related to Alzheimer's."
The content of the research summarized here is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
About the Medical University of South Carolina
Founded in 1824 in Charleston, the Medical University of South Carolina (MUSC) is the oldest medical school in the South, as well as the state's only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and 700 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state's leader in obtaining biomedical research funds, in fiscal year 2018, MUSC set a new high, bringing in more than $276.5 million. For information on academic programs, visit http://musc.
As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians' practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2019, for the fifth consecutive year, U.S. News & World Report named MUSC Health the number one hospital in South Carolina. To learn more about clinical patient services, visit http://muschealth.
MUSC and its affiliates have collective annual budgets of $3 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care.
About Hollings Cancer Center
The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 200 physicians and scientists and 20 academic departments. It has an annual research funding portfolio of more than $40 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.