Mutations in the gene that encodes a protein called adenine nucleotide translocator (ANT) cause a variety of conditions, such as heart disease and weakness of the eye muscles, but the underlying mechanism of how these mutations trigger disease has been unclear. Now, researchers discovered that ANT is critical for a quality control process called mitophagy--which helps to ensure the integrity of the mitochondria network by removing damaged mitochondria--and found that mutations that lead to a defective quality control system ultimately cause heart disease.
The findings, published in Nature, reveal the new and surprising function of ANT, a well-known protein that also contributes to the mitochondria's ability to produce the chemical energy, or adenosine triphosphate (ATP), needed to fuel the body's cells. Although it's been known the mutations in the ANT gene cause diseases, including cardiomyopathy--a disease that makes it harder for one's heart to pump blood to the rest of the body--research has shown that the mutations do not impact ANT's ability to produce chemical energy, raising questions about how one would then get a disease.
"In revealing the link between ANT and mitophagy, and the impact mutations have on quality control, our findings change the way we think about the disease-causing mutations and enable us to focus our attention on the right pathway," said the study's corresponding author. "Now that we know these diseases are caused by defective quality control rather than a lack of ATP generation, we can start thinking about therapeutic approaches that improve the quality control."
Mitochondria, known as the powerhouse of the cell, generate most of the ATP needed to fuel body's cells and play an important role in high-energy demanding organs, including the heart and liver. Quality control mechanisms, including mitophagy--which often occurs to defective mitochondria following damage or stress--help to ensure the mitochondrial network functions properly. Although the role of mitophagy has been established, there has been limited information, until now, about the different proteins that participate in mitophagy.
To gain a deeper understanding of the components involved in mitophagy, the team of researchers conducted a CRISPR/Cas9 genome-wide screening, using multiple reporter systems and pro-mitophagy triggers. To their surprise, they found that ANT is required for the quality control pathway of mitophagy in a number of cell types. In follow-up tests to confirm their findings, researchers found that ANT promotes mitophagy independent of its role in producing ATP, showing that the protein has two distinct jobs.
Upon that revelation, the researchers designed tests to investigate whether mutations in the genes of ANT affected mitophagy. They found that disease-causing mutations in ANT cancel its ability to bind with complexes of proteins that are required for proteins to relocate from the inner-membrane into the mitochondrial matrix, ultimately inhibiting mitophagy. Further studies showed that the genetic removal of ANT suppresses mitophagy. Researchers also found that mice genetically lacking ANT had blunted mitophagy and experienced a profound accumulation of atypical mitochondria.
"We were extremely surprised to find that ANT participates in mitophagy, revealing that it has two separate functions--ATP generation and quality control," the author said. "While there's no magic bullet for improving the quality control process, we hope our findings lay the groundwork for future efforts that examine how to offset the suppression of mitophagy and, ultimately, prevent these mutations from causing disease."
https://www.pennmedicine.org/news/news-releases/2019/october/failure-of-mitochondrial-quality-control-causes-heart-disease
https://www.nature.com/articles/s41586-019-1667-4
Failure of mitochondrial quality control causes heart disease
- 1,171 views
- Added
Edited
Latest News
Metabolic rewiring promotes…
By newseditor
Posted 18 Apr
A drug to prevent flu-induc…
By newseditor
Posted 18 Apr
New origin of deep brain waves
By newseditor
Posted 17 Apr
Starving cells hijack prote…
By newseditor
Posted 17 Apr
Miniature battery-free epid…
By newseditor
Posted 17 Apr
Other Top Stories
Artificial intelligence for diagnosing dementia
Read more
Protecting the brain from dementia-inducing abnormal protein aggreg…
Read more
Miniature, implantable nerve coolers for targeted pain relief
Read more
Sex differences in the alcohol mediated brain activity
Read more
A novel therapy using unique thermogel prevents retinal scarring
Read more
Protocols
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Modular dual-color BiAD sen…
By newseditor
Posted 31 Mar
Publications
How does the microbiota con…
By newseditor
Posted 18 Apr
The integrated stress respo…
By newseditor
Posted 18 Apr
The immunobiology of herpes…
By newseditor
Posted 17 Apr
Circulating microbiome DNA…
By newseditor
Posted 17 Apr
Spindle oscillations in com…
By newseditor
Posted 17 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar