Researchers at the Hospital for Sick Children (SickKids) report that mitochondria depend on a newly discovered recycling mechanism. Their research demonstrates mitochondria can recycle a localized injury, removing damaged folds called cristae that contain proteins and molecules needed for energy production. The researchers believe this mechanism could present a future target for the diagnosis and treatment of conditions characterized by mitochondrial dysfunction, including infections, fatty liver disease, aging, neurodegenerative conditions, and cancer.
The findings are published in Nature in an article titled, “Lysosomes drive the piecemeal removal of mitochondrial inner membrane.”
“Mitochondrial membranes define distinct structural and functional compartments,” the researchers wrote. “Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodeling, but the significance of this compartmentalized organization is unknown. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle.”
“Our research shows, for the first time, that mitochondria are able to recycle a localized injury, removing damaged cristae, and then function normally afterward,” explained Nicola Jones, MD, PhD, staff physician and senior scientist in the cell biology program at SickKids and lead of the study.
In cells, structures called lysosomes act as recycling centers that can digest different kinds of molecular material. Using microscopes at the SickKids Imaging Facility, Akriti Prashar, PhD, a postdoctoral fellow in Jones’ lab and first author on the paper, identified that a mitochondria’s damaged crista can squeeze through its outer membrane to have a lysosome directly engulf it and break it down successfully.
The researchers named the process VDIM formation, which stands for vesicles derived from the inner mitochondrial membrane. By removing damaged cristae through VDIMs, cells can prevent harm from spreading to the rest of the mitochondria and the whole cell.
“We believe that VDIMs could be a way of protecting cells from health conditions that affect mitochondria, such as cancer and neurodegeneration,” Prashar said.
The research team, including scientists at the Francis Crick Institute and Johns Hopkins University, found that forming a VDIM involved several steps and molecules. First, a damaged crista releases a signal that activates a channel on the nearby lysosome to allow calcium to flow out of the lysosome. Calcium then activates another channel on the outer membrane of the mitochondria to form a pore and allow damaged cristae to squeeze out of the mitochondria into the lysosome, which digests the damaged material—something that has never been seen before. By recycling just the damaged crista, mitochondria can continue their regular function.
“Understanding this process gives us insight into how mitochondria stay healthy, which is important to everyone’s overall health and longevity,” added Prashar.
The researchers hope to explore how altering VDIM formation could improve symptoms or even prevent health conditions caused by underperforming or damaged mitochondria.
