What Mitochondrial Cristae Are Telling Us About HIV-associated Neurological Disorder

Mitochondria are small intracellular organelles with a diameter about the size of a few microns. They serve crucial functions for cells such as the production of energy in the form of ATP and control levels of intracellular Ca2+. Muscle cells and neurons are particularly dependent on mitochondria integrity for their survival as these cells require a high demand of energy to function. Thus, it should not be surprising that mitochondria damages lead to cardiac diseases and neurological disorders, such as Alzheimer’s and Parkinson’s diseases.

Mitochondria are dynamic organelles that move inside cells, divide independently from the cell cycle, fuse and change morphology during their life. Their shape can change through the combined action of two processes called fission and fusion. Mitochondrial fission promotes the renewal of mitochondria and their proliferation whereas fusion allows mitochondria to interact with each other and elongate, facilitating mitochondrial movement and distribution. Through these transformations, mitochondria modulate their functions.

For instance, elongation is often linked to increased ATP production and energy for the cell. When there is high demand for energy, mitochondria divide. Energy production by mitochondria is regulated by an inner membrane. This inner membrane folds creating cristae (Fig. 1A, white arrow). Cristae are specialized bag-like compartments for the diffusion of molecules that are essential for the ATP production. Cristae are also loaded with proteins involved with ATP production, such as ATP synthase.

Neurons are highly energy-dependent cells and require ATP at distant regions such as axonal and dendritic synapses. Mitochondria help neurons meet the high energy demands by traveling across a long distance. Healthy mitochondria are particularly important for the survival of neurons as revealed by the correlation between neurological diseases and mitochondrial damaged and disrupted cristae. A disease that has recently been linked to a deficit in mitochondrial function is human immunodeficiency virus type-1 (HIV) -associated neurocognitive disorder (HAND).

HAND, which is caused by HIV infection of brain cells, is characterized by significant impairments in executive function, memory, attention, multitasking, and judgment. Such neurological alterations could be related to the ability of HIV to alter how neurons communicate with each other through synapses. The role of mitochondria in the etiology of HAND is still under investigation. Interestingly, postmortem brains of HIV-positive individuals with HAND exhibit signs of impaired mitochondrial metabolism.

Furthermore, when compared to brains of HIV positive subjects with no cognitive alterations (Fig. 1A), HAND brains contain mitochondria with abnormal morphology, exemplified by the loss of cristae (Fig. 1B). The question remains as to how HIV promotes mitochondrial impairment. This is an important issue because even with the advent of combined antiretroviral therapy to diminish HIV viral load, over 50% of HIV patients in the United States still develop HAND symptoms. Notably, clinical studies have shown that some drugs composing the cocktail of the antiretroviral therapy can damage mitochondria.

It is important to recall that HIV does not infect neurons and thus, it cannot directly damage neuronal mitochondria. Yet, experimental evidence has shown that several viral proteins induce mitochondrial damage. These proteins, which are produced by infected cells, affect mitochondrial function in different ways.

For instance, the HIV envelope protein gp120, which is crucial for the entry of the virus into cells, reduces mitochondrial movements and the production of ATP. This protein, when expressed in mouse brain, increases the size of mitochondria, which appear elongated and with fewer cristae (Fig. 1D) when compared to mice control (Fig. 1C). Furthermore, the HIV transcription activator, Tat, reduces mitochondria function by altering the fission process and decreasing mitochondrial membrane potential, which is an index of the capacity of mitochondria to generate ATP.

Defects in mitochondrial movements and perturbations to their energy production are known to impair neuronal function and have been linked to neurodegenerative diseases. The recent discovery that the function and morphology of neuronal mitochondria in HAND subjects are altered has expanded the interest in mitochondrial research pertaining to neurological alterations caused by HIV. Indeed, mitochondrial biology could be a new critical area of investigation to the development of a new therapy for HIV positive subjects.

These findings are described in the article entitled Human Immunodeficiency Virus Promotes Mitochondrial Toxicity, published in the journal Neurotoxicity Research. This work was led by Italo Mocchetti from Georgetown University Medical Center.

About The Author

Italo Mocchetti

Neurotrophic factors, and especially the neurotrophins, are proteins known to play a key role in neuronal repair, maintenance and differentiation as well as to model our neuronal circuitry. Therefore, neurotrophins are essential to our ability to move, feel and think. The primary focus of Dr. Mocchetti's research program at Georgetown University is to study the neurobiology of the neurotrophins. The ultimate goal of such program is to use these proteins as potential biotherapies for human neurological disorders, such as Alzheimer's and Parkinson's diseases, stroke, trauma and AIDS dementia. Specifically, Dr. Mocchetti’s group is characterizing the neuroprotective effects of a major neurotrophin, Brain-Derived Neurotrophic Factor (BDNF). Using neuronal cultures, viral vectors and mutant mice, they have recently demonstrated that BDNF reduces neuronal cell death evoked by HIV-1 proteins, most likely by down-regulating chemokine receptors responsible for mediating viral neurotoxicity. Based on these results, Dr. Mocchetti's group is currently studying synthetic compounds that mimic the neurotrophic effect of BDNF while being able to cross the blood brain barrier (BBB). Using transfected cell lines and technique probing different signal transduction pathways, his group has recently demonstrated that gangliosides, compounds able to cross the BBB, indeed mimic the neurotrophic effects of the neurotrophins. These exciting results raise a legitimate hope that gangliosides and potentially other compounds yet to be identified could be used as therapeutic tools in neurodegenerative diseases.

Comment (1)

Speak Your Mind!

READ THIS NEXT

Holographic Picture Of Quantum Matter: From Black Holes To Quark-gluon Plasma

One of the central problems in the modern high energy physics is related to our ability to describe and explain the behavior of the quark-gluon plasma ‚Äď a state of matter which occurs when gold or lead nuclei collide at very high energies. At temperatures of about trillions of kelvins the quarks, that make up […]

From Quantum Bit Commitment To The Reality Of The Quantum State

Quantum mechanics famously enables certain cryptographic tasks that would be classically impossible, among them, distributing a string of bits between two or more players unconditionally securely and enabling a secret to be split and distributed securely. The reason that quantum mechanics empowers cryptography is embodied in a number of no-go results: the fact that an […]

Reducing Unnecessary Tests And Interventions for Bronchiolitis

Bronchiolitis is a viral airway infection that is very common in young children, caused mainly by the respiratory syncytial virus (RSV). Whereas RSV can affect anyone and causes mainly the symptoms of a common cold in adults and older children, younger children can be affected more seriously. In young children, especially infants less than one-year-old, […]

Banana Spider: Facts And Photos

“Banana spider” is a colloquial name for spiders in the genus¬†Nephila,¬†also known by the common name¬†golden silk orb-weavers. Spiders in the genus¬†Nephila are known for their bright colors, long spindly leg appearance, and impressive web structures that can range up to 1.5¬†meters in diameter.¬† The name “nephila” comes from the ancient Greek¬†nein (to weave) + […]

Exploring The “Nordic Paradox” Of Violence Against Women In Countries With High Gender Equality

Violence against women by their intimate partners is a major public health problem globally and remains even more so in western societies. Gender inequality has been considered a factor in explaining violence against women. However, although high levels of gender equality are expected to be linked to a lower prevalence of intimate partner violence against […]

Cursive Handwriting: Tips And Practice Sheets

There can be no doubt that cursive writing is not as popular as it once was. But, if you are learning cursive handwriting, we have some tips and practice sheets for you. Good penmanship can be considered an art form and, like every other art form, mastering it requires a lot of practice. If you […]

Symmetrical Resonators Leads To Extraordinary Acoustic Transmission

If we imagine a plate, which is perfectly reflective of sound and drill holes through 5% of its surface then we would expect 5% of the sound energy to be transmitted and the rest reflected.¬† While this would be true on average, what we would instead observe is that for certain critical frequencies most of […]