MITOCHONDRION MALFUNCTION: Almost every cell in the body depends on specialized organelles called mitochondria, pictured here. Parkinson's disease may be linked to poor mitochondrial function in brain cells. Image: Wikimedia Commons
In the past researchers have observed an association between poor mitochondrial function and Parkinson's disease, a neurodegenerative disorder of the central nervous system that impairs speech and motor functions and affects five million people worldwide. A new meta-analysis suggests that low expression levels of 10 related gene sets responsible for mitochondrial machinery play an important role in this disorder—all previously unlinked to Parkinson's. The study, published online today in Science Translational Medicine, further points to a master switch for these gene sets as a potential target of future therapies.
Mitochondria, specialized organelles found in nearly every cell of the body, use cellular respiration to generate one of the most important sources of chemical energy—adenosine triphosphate (ATP), a versatile nucleotide that powers everything from cell division to cell signaling to transportation of large molecules across the cell membrane. Because mitochondria are so vital to a cell's normal functions, damaged and dysfunctional mitochondria have been implicated in a wide array of diseases and disorders, such as diabetes and schizophrenia. Brain tissue is particularly susceptible to mitochondrial deficits because neurons generally have high-energy requirements.
Charleen Chu, a neuropathologist at the University of Pittsburgh School of Medicine who has studied the link between mitochondrial function and Parkinson's, but was not involved in the new study, called it " a very interesting paper," adding that the massive study "indicates that mitochondrial dysfunction occurs early and for whatever reason mitochondrial biogenesis is either impaired or not stepping up to the demand of the neurons."
In a three-stage meta-analysis, Harvard University neurologist Clemens Scherzer and his collaborators analyzed gene expression in 410 samples taken from patients that either had symptomatic or asymptomatic Parkinson's or were healthy, including 185 samples of substantia nigra—a midbrain region where dopamine neurons are particularly susceptible to degeneration.
Their analyses suggest that underexpression of 10 specific gene sets—groups of genes that encode the same biological pathway or process—are consistently associated with Parkinson's. These 10 sets encode proteins responsible for four related bioenergetic processes: nuclear-encoded mitochondrial electron transport (the key energy-extracting operation), mitochondrial biogenesis (by which new mitochondria are formed) as well as glucose utilization and glucose sensing (processes by which glucose levels are evaluated and modified). The researchers note that their findings point to more widespread deficits in mitochondrial function compared with earlier studies. In particular, the analysis found deficiencies in almost all the protein complexes from which the cellular electron transport chain is constructed.
"A deficit in complex I in the electron transport chain has been thought to be a cause of Parkinson's for a long time, but it was never clear how generalizable this was," Scherzer says. "What we found is that on a molecular level, the complex I deficit is probably just the tip of the iceberg of a pervasive deficit in all energy genes."
A protein called peroxisome proliferator–activated receptor g co-activator 1-alpha (PGC1-alpha) regulates the expression of many genes identified by the researchers. The team tested whether overexpression of PGC1-alpha could protect cultures of rat brain cells from the pesticide rotenone, which inhibits complex I of the electron transport chain in neuronal mitochondria and produces many symptoms similar to those of Parkinson's. They found that activating PGC1-alpha decreased cell damage and death, blocking some of rotenone's neurotoxicity. These findings suggest that similar modification of the regulating protein could be a viable form of future therapy for Parkinson's. Earlier research has shown that environmental factors, including pesticide exposure, may aggravate inherited deficiencies in mitochondrial function, possibly explaining some cases of Parkinson's disease.
"The most exciting result is the discovery of PGC1-alpha as potential new target of therapy for early intervention Scherzer," says. "It's a master switch that turns on hundreds of genes necessary to build the powerhouse machinery of the cell." Currently there is no cure for Parkinson's, but the disease can be managed through deep-brain stimulation surgery, physical therapy and medications that increase dopamine signaling in the brain.
Chu says the study emphasizes that healthy cells need more than functional mitochondria—they need to support a kind of mitochondrial life cycle that involves continuous genesis, repair and recycling. "It's possible that interference at any one stage of recycling and maintaining healthy mitochondria could lead to Parkinson's," she says. "Neurons are especially dependent on mitochondria for metabolism."