Elsevier

Mitochondrion

Volume 56, January 2021, Pages 40-46
Mitochondrion

Mitohormesis; Potential implications in neurodegenerative diseases

https://doi.org/10.1016/j.mito.2020.11.011Get rights and content

Abstract

Mitochondrial dysfunction is known to be associated with neurodegenerative diseases (NDDs), which is a major burden on the society. Therefore, understanding the regulation of mitochondrial dysfunctions and its implication in neurodegeneration has been major goal for exploiting these mechanisms to rescue neuronal death. The crosstalk between mitochondria and nucleus is important for different neuronal functions including axonal branching, energy homeostasis, neuroinflammation and neuronal survival. The decreased mitochondria capacity during progressive neurodegeneration leads to the altered OXPHOS activity and generation of ROS. The ROS levels in narrow physiological range can reprogram nuclear gene expression to enhance the cellular survival by phenomenon called mitohormesis. Here, we have systematically reviewed the existing reports of mitochondrial dysfunctions causing altered ROS levels in NDDs. We further discussed the role of ROS in regulating mitohormesis and emphasized the importance of mitohormesis in neuronal homeostasis. The emerging role of mitohormesis highlights its importance in future studies on intracellular ROS mediated rescue of mitochondrial dysfunction along with other prevailing mechanisms to alleviate neurodegeneration.

Section snippets

Mitochondrial dysfunction and neurodegeneration

Neurodegenerative diseases (NDDs) includes spectrum of disorders characterized by progressive loss of neurons in central and peripheral nervous system (Ellis and Fell, 2017, Jellinger, 2010, Hoogendam, 2017). These include range of neuronal pathologies where PD and AD are most prevalent affecting 8% population worldwide increasing socioeconomic burden of society (Association, 2019). Other NDDs such as multiple sclerosis (MS), Huntingtońs disease (HD), amyotrophic lateral sclerosis (ALS),

ROS levels in neuronal pathologies

Oxidative stress observed in various neuronal pathologies is due to excess of reactive oxygen species (ROS) which leads to persistent or reversible cellular damage (Singh et al., 2019, Tönnies and Trushina, 2017, Gandhi and Abramov, 2012.). The majority of existing molecular mechanism for oxidative stress suggest imbalance between levels of oxidants and antioxidants (Singh et al., 2019). Brain is the organelle which is highly metabolically active and is more vulnerable to oxidative stress (

Mitohormesis: ROS as an important signaling molecule

ROS are generally considered to have short life and consist of highly reactive radicals, peroxides, radical anions, and combinations of them, including singlet oxygen (1O2), superoxide radical anion (O2•–), hydrogen peroxide (H2O2), hydroperoxyl radical (HO2), hydroxyl radical (OH), hydroxyl anion (OH), peroxide radical anion (O22–), peroxyl radicals (RO2 ) and others (Hoogendam, 2017, Bolisetty and Jaimes, 2013)). As ROS are highly reactive, they quickly react with biological molecules

Nuclear-mitochondrial crosstalk

A typical human cell is comprised of multiple subcellular compartments which are membrane bound organelles. Though each organelle has been viewed as individual entities and allotted specific functions, it still requires extensive inter organelle communication to maintain normal cellular operation (Shai, et al., 2018, Valm, 2017, Keenan et al., 2020). This communication mostly requires contact sites for this purpose, or it can be relay of signals by means intermediates (Höglinger, 2019,

Nuclear encoded miRNAs translocate to mitochondria: Possible role in mitohormesis

The transport of nuclear encoded RNAs to mitochondria is one of the mechanisms which regulate mitochondrial capacity in different patho-physiological conditions (Jeandard et al., 2019, Kamenski et al., 2019, Abbott et al., 2014). Interestingly small noncoding RNAs including miRNAs have been shown to translocate to mitochondria; however, the role of these miRNAs in various stress conditions have not been investigated yet. miRNAs belong to family of small noncoding RNAs, which play an important

Mitohormesis benefits neurons

Although mitohormesis have not been studied extensively in different disease models, there are few reports which suggest the role mitohormesis in tumor cell survival and promoting metastasis under cancerous condition (Bao, 2015, Kenny, 2019) . This recent report showed that mitohormesis primes a subpopulation of cancer cells to basally upregulate mitochondrial stress responses, which include the mitochondrial unfolded protein response(UPRmt) providing an adaptive metastatic advantage (Kenny,

Concluding remarks

The maintenance of healthy brain and prevention/delay of neurodegeneration have been the goal for ageing research. Several studies from the last decade have shown role of mitochondrial ROS in neurodegeneration and its impact on aging, which led to development and establishment of free radical theory of ageing (FRTA) (Yun and Finkel, 2014). According to FRTA, ageing and neurodegeneration are primarily caused by mitochondrial mediated generation of ROS (Lagouge and Larsson, 2013, Stefanatos and

CRediT authorship contribution statement

Dhruv Gohel: Conceptualization, Methodology, Writing - original draft. Rajesh Singh: Supervision, Conceptualization, Writing - review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The research for mitochondrial involvement in NDDs was financially supported by multiple funding agencies including Department of Science and Technology (DST, India), Department of Biotechnology (DBT, India), Indian Council of Medical Research (ICMR) and SERB (Science and Engineering Research Board, India) to Prof. Rajesh Singh. Dhruv Gohel has received Senior Research Fellowship (Ref No: 3/1/2/126/Neuro/2019-NCD-1) from Indian Council of Medical Research (ICMR). Authors also acknowledge the

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