Considering Mitochondria and Neurodegeneration

Since mitochondria seem to be the dominant theme this week, today I thought I’d point out a couple of recent open access papers that focus on the role of mitochondrial function (and dysfunction) in the neurodegeneration that accompanies aging. Every cell bears a swarm of mitochondria, the descendants of ancient symbiotic bacteria. Even though mitochondria long ago evolved into integrated cellular components, they still behave very much like bacteria in many ways. They multiply through division, and can fuse together and swap component parts, pieces of the molecular machinery necessary to their function. They also contain their own DNA, distinct from that of the cell nucleus.

The primary role of mitochondria is to undertake the energetic process of packaging chemical energy store molecules to power cellular operations. This is of particularly importance to energy-hungry tissues such as the brain, and why mitochondrial dysfunction with advancing age is thought to be especially relevant to neurodegenerative conditions. The evidence for this is more clear or less clear depending on which condition is discussed. In Parkinson’s disease, for example, it is very evident that mitochondrial function is central to the characteristic loss of specialized neurons that drives the condition. For Alzheimer’s disease, on the other hand, it is a real challenge to talk about the degree to which the numerous involved mechanisms are more or less important than one another. There is a lot of conflicting evidence.

The decline of mitochondrial function with age appears to have several distinct causes, not all of which are fully understood. Quality control mechanisms responsible for destroying errant and worn out mitochondria become less effective in later life. Some forms of mitochondrial DNA damage can produce mitochondria that are more resilient to quality control or more able to replicate than their peers, and they can take over cells to make them malfunction and cause harm. But aside from this, all mitochondria change profoundly in activity and structure in older individuals, and this may be a broad reaction to rising levels of molecular damage or other changes in signaling and cell behavior, above and beyond issues caused by failing quality control.

Brain Mitochondria, Aging, and Parkinson’s Disease

High energy requirements tissues such as the brain are highly dependent on mitochondria. Mitochondria are intracellular organelles deriving and storing energy through the respiratory chain by oxidative phosphorylation. In a single neuron, hundreds to thousands of mitochondria are contained. Non-inherited mitochondrial DNA (mtDNA) mutations are called somatic mutations and appear over time. Mutated mtDNA replication is better when compared to wild-type mtDNA, which facilitates its clonal expansion. Once mutated mtDNA reaches at least 60%, the cell will have deficient respiration and will accumulate additional mtDNA mutations until cell death.

Somatic mtDNA mutations are important in aging and disease such as Parkinson’s disease (PD). PD results mostly from the loss of dopaminergic neurons in the substantia nigra (SN). SN dopaminergic neurons are lost in an age and mitochondrial dysfunction related way. When compared to other neurons, SN dopaminergic neurons have more mtDNA deletions, where the load of mtDNA mutations parallels the deficiency of the respiratory chain.

Aging, at the cell level, is an increasingly incapacity to recycle organelles and macromolecules. Mitochondria DNA is very vulnerable. The aging process is tightly linked to mtDNA deletions and point mutations and to reactive oxygen species (ROS). Additionally, mtDNA deletions and point mutations accumulate over time. This leads to energetics impairment, increased ROS production, mtDNA lesions, and the decline of mitochondrial respiration.

Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism?

The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress.

To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded and aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (of expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurodegenerative diseases such as Alzheimer’s, Parkinson’s or even Huntington’s diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.

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