Study opens new therapeutic avenue for mitochondria malfunction

October 25, 2018

(PHILADELPHIA)--A surprising offender has been emerging to drive the progression of Parkinson's, Alzheimer's, Huntington's and other neurodegenerative diseases: calcium. Calcium controls the production of fuel in mitochondria, the cell's powerhouses. But too much calcium can lead to cellular damage and even cell death. These events can cascade into neurodegenerative diseases and causes injury to the brain and heart during strokes and heart attacks.

Now, researchers at Jefferson (Philadelphia University + Thomas Jefferson University) have identified a molecular lock and key that control calcium's entry into mitochondria, and show how the key competes with a potent calcium-blocking compound. The finding reveals a new target for drug discovery.

"Our study gets directly to the pharmacologic and potential medical targeting of mitochondrial calcium uptake," said senior author Gyorgy Hajnoczky, MD, PhD, Director of the MitoCare Center, and Professor in the department of Pathology, Anatomy and Cell Biology at the Sidney Kimmel Medical College at Jefferson.

The work, another successful MitoCare Center collaboration, published October 25 in the journal Molecular Cell, with first author Melanie Paillard, PhD, a postdoctoral fellow in Hajnoczky's lab, and Gyorgy Csordas, MD and Suresh K Joseph, PhD, both professors at the MitoCare Center.

To control calcium's entry, mitochondria have specialized doors called mitochondrial calcium uniporter complexes. The doors have many parts including the pore through which calcium enters, called MCU, and a sort of gatekeeper protein that detects when calcium is at the door, called MICU1. When calcium levels are low, MICU1 keeps the doors closed. But when a surge of calcium arrives--as it does with each heartbeat, for example--MICU1 opens the door to the mitochondria. Dr. Hajnoczky and his colleagues wanted to understand how the MICU1 gatekeeper keeps the MCU pore closed.

Because calcium overload in mitochondria is implicated in multiple diseases, such as strokes and heart attacks and MCU controls calcium's entry, researchers are on the look out for compounds that block MCU's opening. The most effective compounds used in laboratories are ruthenium red and ruthenium 360. The drugs lock onto a section of the MCU pore to prevent calcium entry.

In a surprise finding, Dr. Hajnoczky's team discovered that the MCU pore has a deadbolt that can lock/open the door when a small part of the gatekeeper MICU1 interacts with it as a key. Ruthenium red/360 works as an alternative key for the same deadbolt to lock the door; thus competing with the gatekeeper MICU1. Ruthenium red/360 was able to block calcium much more effectively in liver cells that lacked the MICU1 gatekeeper protein, than in cells whose MICU1 was present.

Human heart tissue contains far less MICU1 than other tissue, suggesting that compounds like ruthenium red/360 might be more selectively in blocking calcium there. "We found that the dose response for the drugs totally depends on the presence of MICU1," said Dr. Hajnoczky. The researchers then confirmed the results in two other kinds of cells. The discovery suggested MICU1 attaches to the same location on MCU as the drugs.

Because ruthenium compounds attached to an area of the MCU known as DIME, the researchers looked for a similar area of attachment on the MICU1. They found a section of MICU1 that fits with MCU like a key to a lock. Mutating this area of MICU1, which the researchers named DIME Interacting Domain, or DID, reduced its ability to connect with MCU and prevented MICU1 from regulating calcium entry into mitochondria. Cells with mutant MICU1 were unable to manage the calcium levels in mitochondria, which led to oxidative stress and cellular damage. The results indicate MICU1 attaches directly to the MCU and mitochondria need the DID region of MICU1 to control calcium levels and thus cell survival.

The team's results open a possible new avenue for therapies that control mitochondrial calcium levels. "Targeting the interaction of MICU1 with MCU is highly relevant for drug designing efforts," said Dr. Hajnoczky. "For diseases where mitochondria malfunction and cause cell death, a drug that blocks calcium entry might improve the patient outcomes."
-end-
This article was supported by NIH grant RO1 GM102724. The authors report no conflict of interest.

Article reference: Melanie Paillard, Gyorgy Csordas, Kai-Ting Huang, Peter Varnai, Suresh K. Joseph and Gyorgy Hajnoczky, "MICU1 interacts with the D-ring of the MCU pore to control its Ca2+ flux and sensitivity to Ru360," Molecular Cell,DOI: 10.1016/j.molcel.2018.09.008, 2018.

Media Contact: Edyta Zielinska, edyta.zielinska@jefferson.edu, 215-955-7359.

Thomas Jefferson University

Related Mitochondria Articles from Brightsurf:

Researchers improve neuronal reprogramming by manipulating mitochondria
Researchers at Helmholtz Zentrum M√ľnchen and Ludwig Maximilians University Munich (LMU) have identified a hurdle towards an efficient conversion: the cell metabolism.

Inside mitochondria and their fascinating genome
EPFL scientists have observed -- for the first time in living cells -- the way mitochondria distribute their transcriptome throughout the cell, and it involves RNA granules that turn out to be highly fluid.

'Cheater mitochondria' may profit from cellular stress coping mechanisms
Cheating mitochondria may take advantage of cellular mechanisms for coping with food scarcity in a simple worm to persist, even though this can reduce the worm's wellbeing.

A ribosome odyssey in mitochondria
The ciliate mitoribosome structure provides new insights into the diversity of translation and its evolution.

Fireflies shed light on the function of mitochondria
By making mice bioluminescent, EPFL scientists have found a way to monitor the activity of mitochondria in living organisms.

First successful delivery of mitochondria to liver cells in animals
This experiment marks the first time researchers have ever successfully introduced mitochondria into specific cells in living animals.

Lack of mitochondria causes severe disease in children
Researchers at Karolinska Institutet in Sweden have discovered that excessive degradation of the power plants of our cells plays an important role in the onset of mitochondrial disease in children.

Unexpected insights into the dynamic structure of mitochondria
As power plants and energy stores, mitochondria are essential components of almost all cells in plants, fungi and animals.

Mitochondria are the 'canary in the coal mine' for cellular stress
Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery.

Master regulator in mitochondria is critical for muscle function and repair
New study identifies how loss of mitochondrial protein MICU1 disrupts calcium balance and causes muscle atrophy and weakness.

Read More: Mitochondria News and Mitochondria Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.