Reappraisal Of Metabolic Dysfunction in Neurodegeneration: Focus On Mitochondrial Function And Calcium Signaling Part 7

Peroxisomal lipid metabolism

Metabolic dysregulation associated with peroxisome dysfunction may contribute to the development of NDDs. 

Oxisomes, also known as oxidosomes or catalase, are special subcellular organelles in cells that can use oxygen to convert oxides into water and oxygen. Exosomes play an important metabolic and defensive role in many organisms and are also related to many physiological processes.

Research in recent years has shown that the relationship between exosomes and memory has also received increasing attention. Some studies have found that the distribution and function of exosomes in the brain are closely related to cognitive processes. Specifically, exosomes can remove harmful substances such as free radicals and peroxides in cells, thereby protecting the stability and normal functioning of neurons.

In addition, many external stimuli and internal abnormal states can affect the number and activity of exosomes, thereby affecting memory ability. For example, long-term exposure to environmental pollution, radiation, and lack of oxygen can reduce the level of exosomes, increase free radicals and oxidative damage, and then damage the health and signal transduction of neurons, ultimately leading to memory impairment and cognitive decline.

On the contrary, proper exercise, diet, psychological relief, and adequate oxygen can promote the development and activity of exosomes, thereby improving the metabolic and signal transduction efficiency of neurons, and improving memory ability and cognitive function. In addition, studies have also found that some natural compounds and drugs, such as vasopressin and some health products, can also promote the development and activity of oxidases, thereby improving memory and cognitive function.

In summary, there is a close relationship between oxidases and memory. In daily life, we should pay attention to protecting and promoting the level and activity of oxidases, adopt a healthy lifestyle, and reasonable drug intervention to improve memory and cognitive function. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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Peroxisomes are highly dynamic and important metabolic organelles that can directly communicate with mitochondria and contribute to cellular lipid metabolism, e.g., the oxidation of very-long-chain fatty acids (VLCFAs), synthesis of phospholipids, such as plasmalogen/ether lipids (myelin sheath lipids) and docosahexaenoic acid (DHA), and the regulation of redox and inflammatory signaling. 

Furthermore, the brain is a lipid-rich organ, and myelin sheaths are rich in plasmalogens/ether lipids synthesized in peroxisomes. Therefore, slight alterations in peroxisomal lipid metabolism may represent significant mechanisms contributing to changes in neuronal function (reviewed in [401]). 

In AD, alternations in lipid homeostasis/peroxisome function include significantly decreased levels of plasmalogens and DHA and increased levels of VLCFA. The severity of these alternations correlates with the progression of the disease [402, 403] and has been shown to change cell membrane properties and increase intracellular cholesterol levels. 

These changes increase β-secretase and γ-secretase activities, resulting in enhanced Aβ generation, tau hyperphosphorylation, synaptic dysfunction, and neuroinflammation [404, 405]. 

In addition, peroxisomal β-oxidation inhibition increased Aβ generation in rat brains (reviewed in [405]). Similarly, severe alterations in lipid composition (reductions in DHA and plasmalogens) of frontal cortex lipid rafts from PD patients have been reported [406]. Reductions in ether lipids decreased Ca2+-dependent neurotransmitter release and the respiratory capacity of synaptic mitochondria [407]. 

Therefore, the decrease of ether lipids in mitochondrial membranes might disrupt OxPhos complexes and thus ATP generation sufficiently to compromise neurotransmission. 

However, overall the role of peroxisomal lipid metabolism in NDDs is poorly described. Further studies are required to determine whether peroxisomal lipid dysfunction directly contributes to disease etiology or is a secondary phenomenon. We refer the reader to another recent review for a detailed overview of the peroxisomal lipid metabolism in NDDs and its metabolic cooperation with mitochondria [405, 408]. 

Modulation of mitochondrial function as a possible therapeutic target for neurodegeneration As discussed earlier, dysregulation in mCa2+ homeostasis might be an upstream event causing mitochondrial dysfunction in NDDs. 

For this reason, various combinations of modulators aimed at targeting or correcting defects in mCa2+ exchange or restoring mitochondrial function/ energy metabolism may serve as therapies to prevent the development of NDDs. Possible therapeutic strategies, summarized in Table 1, include reducing mCa2+ uptake, enhancing mCa2+ reflux, and preserving mitochondrial architecture/functions (such as the assembly of respiratory chain complexes and the ATP synthase), bioenergetics, axonal transport of mitochondria, and mitochondrial proteostasis. 

However, it is still unclear whether increasing mCa2+ reflux or reducing mitochondrial mCa2+ uptake will be superior for neuroprotection. Both are sufficient to limit mCa2+ overload and correct mCa2+ dysregulation. 

Still, a few points need careful consideration, such as if modulators of mitochondrial mCa2+ homeostasis will negatively impact Ca2+-dependent physiological functions, such as TCA cycle flux and mitochondrial dynamics. 

It should also be noted that different NDDs might have disease-specific regulation of mtCU channel activity, which requires more detailed experimentation. Beyond this, cellular heterogeneity in mitochondrial function should also be considered; for example, axonal and synaptic mitochondria are reported to be involved in Ca2+ buffering and presynaptic transmission, whereas the soma is the primary site for mitochondrial quality control. 

Therefore, a proper understanding and regulation of the MCU, or a combination of modulators that aim to increase mCa2+ buffer capacity and still maintain energetics may be necessary to maintain efficient synaptic transmission and effectively treat NDDs.

Challenges, conclusions, and future research directions

A more detailed and nuanced understanding of the cellular and molecular mechanisms altering neuronal mitochondrial metabolism in NDDs is still needed. Several challenging questions remain to be answered, such as (1) How can mitochondrial defects be central in so many different NDDs with diverse etiologies and pathologies? (2) How does mitochondrial dysfunction contribute to protein aggregation? 

(3) Do metabolic defects cause neurodegeneration, or does neuronal dysfunction result in metabolic defects? (4) What are the cellular and molecular events that initiate mitochondrial dysfunction in neurodegeneration? 

(5) How do neurons sense bioenergetic crisis during stress or in pathology? (6) How do cell-specific metabolic profiles impact cellular crosstalk in the context of disease progression? 8) What upstream and downstream signaling pathways are involved at the time of bioenergetic crisis in different NDDs? 9) What are the best models to decipher these events for translation into humans? Here we summarized how numerous cellular events that are compromised during neurodegeneration all require high levels of ATP (e.g., postsynaptic signaling, axonal transport, protein clearance mechanisms, and neurotransmission). 

We also reviewed the evidence that supports the notion that mCa2+ and metabolic impairments are primary cellular defects in NDD pathogenesis. Interestingly, all NDDs share common mechanisms of disease pathology and mitochondrial defects may be a central mechanism in NDD progression. 

However, it remains enigmatic how mitochondrial dysfunction contributes directly to protein aggregation and brain region and cell type-specific dysfunction in NDDs and whether mitochondrial dysfunction is causal or the consequence of the underlying pathology. 

Here, we propose a positive feedback loop between mitochondrial defects and disease pathology that explains numerous mechanisms of NDDs. It's plausible that early mitochondrial dysfunction directly affects protein aggregation through ATP-dependent proteostasis machinery (protein synthesis, folding, and degradation) together with oxidative stress and inflammation and promotes cell-type-specific loss due to mitochondrial death signaling or due to metabolic and energetic dysfunction. 

Recent reports suggest that aggregation-prone proteins shuttle to mitochondria and mitochondrial protein quality control may alleviate protein aggregation. 

Mitochondrial dysfunction leading to the failure of mitochondrial proteostasis could be another crucial factor for pathology-specific protein aggregation. For a detailed mechanism by which mitochondrial dysfunction leads to protein aggregation, we refer the reader to other recent reviews [409, 410]. 

A cell type/brain region-specific regulation of mitochondrial function and mCa2+ signaling is lacking and how this contributes to different disease pathologies is entirely unexplored. 

A complete understanding and precise regulation of mtCU function in different NDDs could eventually help define mechanisms in tissue- and cell-type-specific NDDs. 

Another major challenge in NDD research is selecting experimental models that recapitulate the pathological features of human disease. For decades, animal models have been essential because they are sufficient to recapitulate human genetic mutations and mimic critical clinical features. 

These model systems have provided access to define in vivo systemic interactions and study developmental, metabolic, and behavioral outcomes, which is not possible in cellular systems or patients. 

Arguably, discoveries in animal models have led to a better understanding of the molecular mechanisms of disease pathogenesis but failed to translate in humans. 

However, the failure to translate insights gained from mouse models into humans is not always due to the flaws of the animal model per se. For example, many of these studies lacked detailed causal experimentation and did not exclude other variable factors. 

Other viable alternatives that can help recapitulate human pathophysiology such as the study of postmortem human brains and human iPSCs, and organoids may help as translational stepping stones to therapy. 

The postmortem human brain is particularly helpful in quantifying cellular and molecular markers of disease and the pathology of neural processes. However, access to these samples is limited, and the quality of the tissue is impacted by the donor's condition post-mortem, postmortem interval, collection time, and maintenance conditions all of which can introduce confounding variables. 

Human iPSCs are a versatile tool to model human neurons and are suitable for human in vitro studies, such as high-throughput drug screening. Still, they cannot enable in vivo cellular physiology which takes into account organ and cellular crosstalk and the complex milieu of the complete organism. 

We believe an assortment of models, including robust animal models and three-dimensional cellular systems, will help better define the pathogenesis of NDDs and enable more thorough testing of drugs and therapies for clinical translation. 

Indeed, it is critical to generate robust animal models that phenocopy either the familial or non-familial forms of these disorders. 

An increase in proper causal experimental design using robust engineered animal models that recapitulate the complexity of an entire nervous system, including a full complement of neuronal circuits, glial complexity, and the vascular and immunologic components, will provide valuable insight into how mitochondrial metabolism impacts disease pathogenesis. 

In conclusion, a better understanding of metabolic regulation, identification of mitochondrial targets (see Table 1), and determination of the precise temporal order of pathological cellular events are of paramount importance to the development of novel therapeutic targets to combat NDDs.

Abbreviations

NDDs: Neurodegenerative diseases; AD: Alzheimer's disease; PD: Parkinson's disease; HD: Huntington's disease; PET: Positron emission tomography; Aβ: Amyloid-beta; NFTs: Neurofbrillary tangles; OxPhos: Oxidative phosphorylation; ETC: Electron transport chain; PDH: Pyruvate dehydrogenase; α-KGDH: Alpha-ketoglutarate dehydrogenase; ICDH: Isocitrate dehydrogenase; SDH: Succinate dehydrogenase; MDH: Malate dehydrogenase; Δψm: Mitochondrial membrane potential; COX: Cytochrome-c-oxidase; i Ca2+: Intracellular calcium; mtCU: Mitochondrial calcium uniporter channel; mCa2+: Mitochondrial calcium; NCLX: Mitochondrial Na+/Ca2+ exchanger; MCU: Mitochondrial calcium uniporter; mPTP: Mitochondrial permeability transition pore; PMCA: Plasma membrane Ca2+ ATPase; NCX: Na+/Ca2+ exchanger; TRP: The transient receptor potential; VDCC: Voltage-gated calcium channels; AMPAR: α-Amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; mGluR: Metabotropic glutamate receptors; NMDAR: N-Methyl-D-aspartate receptor; NCX: Na+/ Ca2+ exchanger; SOCE: Store-operated calcium entry; IP3R: Inositol 1,4,5-trisphosphate receptor; RYR: Ryanodine receptor; SERCA: Sarco/endoplasmic reticulum Ca2+-ATPase; TCA: Tricarboxylic acid cycle; MAMs: Mitochondrialassociated membranes; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; AMPK: AMP-activated protein kinase; PGC-1α: Peroxisome proliferatoractivated receptor (PPAR)-γ co-activator 1α; mtDNA: Mitochondrial DNA.

Acknowledgments

This work was supported by NIHR01HL136954, R01HL142271, P01HL147841, and P01HL134608 to J.W.E., NIH K99AG065445 to P.J., and NIH F32HL151146 to J.F.G.

Authors' contributions

PJ and JFG wrote the manuscript, and PJ designed and generated the figures. JWE conceived the review and wrote and edited the manuscript. All authors read and approved the final manuscript.

Conflict of interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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