Page 1 of 20
British Journal of Healthcare and Medical Research - Vol. 11, No. 5
Publication Date: October 25, 2024
DOI:10.14738/bjhmr.115.17586.
Kaur, K. K., Allahbadia, G. N. K., & Singh, M. (2024). An Update on Mitophagy Facilitating Substances: Their Future for Facilitating
Healthy Ageing Along with Treating NDG (Parkinson’s Disease; Alzheimer’s Disease), Cancer, Ovarian Ageing: A Mini Narrative
Review. British Journal of Healthcare and Medical Research, Vol - 11(5). 28-47.
Services for Science and Education – United Kingdom
An Update on Mitophagy Facilitating Substances: Their Future for
Facilitating Healthy Ageing Along with Treating NDG (Parkinson’s
Disease; Alzheimer’s Disease), Cancer, Ovarian Ageing: A Mini
Narrative Review
Kulvinder Kochar Kaur
ORCID: 0000-0003-1473-3419
Dr Kulvinder Kaur Centre For Human Reproduction
721, G.T.B. Nagar, Jalandhar-144001, Punjab, India
Gautam Nand K Allahbadia
A Centre for Human Reproductio 672, Kalpak Garden, Perry
Cross Road, Near Otter’s Club, Bandra(W)-400040 Mumbai, India
Mandeep Singh
Swami Satyanand Hospital Near Nawi Kachehri,
Baradri, Ladowali Road, Jalandhar Punjab
ABSTRACT
The elimination of injured mitochondrial constituents via an event called
mitochondrial autophagy (alias mitophagy)is necessary for appropriate
mitochondrial working, Thereby mitophagy is crucial for the health of all the
aerobic animals inclusive of humans.To our misfortune reduction of mitophagy
takes place with age.A plethora of age related diseases for instance
Alzheimer’sdisease, along with Parkinson’s diseases have the properties of accrual
of injured mitochondria in addition to oxidative injury. Thereby utilizing small
molecule pharmacolological agents, for activating mitophagy is an upcoming
approach the treatment of myriad of diseases. Recent studies have isolated natural
agents, as well as synthetic agents which facilitate mitophagy.Categorization of such
substances have been done in the form of mitophagy stimulators inclusive of
i)antioxidants ii)) mitochondrial uncouplers iii) complex I hampering agents iv)
redox manipulators v) metabolic manipulators vi) neuronal manipulators vi)
autophagy manipulators vii) antibiotics along with anti fungal agents viii) reactive
oxygen species(ROS) producers.Their influence on stimulating the prolongation of
life- along with healthspan in addition to mechanistic modes is further illustrated if
acknowledged .Lastly, mitochondrial biogeneration leads to harmony amongst
mitophagy for guaranteeing appropriate mitochondrial network homeostasis.
Intriguingly, mitochondrial biogeneration activation might be caused by akin
molecules stimulating mitophagy for instance, resveratrol in addition to
metformin. Although remarkable work has been undertaken regarding acquisition
of insight regarding such events, plethora of information needs unraveling,
specifically in the context of acquisition of insight of their interassociation at the
level of organism along with evaluation of combination of such agents which target
mitophagy as well as biogeneration. Future asssessment of such field might be
Page 2 of 20
29
Kaur, K. K., Allahbadia, G. N. K., & Singh, M. (2024). An Update on Mitophagy Facilitating Substances: Their Future for Facilitating Healthy Ageing
Along with Treating NDG (Parkinson’s Disease; Alzheimer’s Disease), Cancer, Ovarian Ageing: A Mini Narrative Review. British Journal of Healthcare
and Medical Research, Vol - 11(5). 28-47.
URL: http://dx.doi.org/10.14738/bjhmr.115.17586.
unveiling the manner such combinations might be influencing lifespan along with
healthspan in different biological models.
Keywords: mitophagy, injured mitochondria, Parkinson’s disease, Alzheimer’s disease.
INTRODUCTION
The manner Art portrays the depletion of the non-essential (as per Picasso) akin similarity is
to mitophagy for the mitochondrial networks. Healthy mitochondria are necessary for the
plethora of foundational events in the aerobic cells inclusive of conversion of the biomolecules,
chemical energy to adenosine triphosphate (ATP)- through oxidative phosphorylation
(OXPHOS) [1], generation of heme [2], breakdown of fatty acids viaβ oxidation [3], controlling
calcium [4] in addition to iron homeostasis, as well as regulating cell demise by apoptosis [6].
Furthermore, mitochondria produce reactive oxygen species (ROS), possessing key working in
various cellular in addition to physiological events inclusive of redox homeostasis along with
immunity [7]. Conversely the injured mitochondria result in elimination of ATP [8],
dysfunctional metal ion homeostasis [9], escalated ROS generation [8], along with the activation
of the cell demise via the liberation of cytochrome c [8,10]. Thereby depleting damaged
mitochondria by an event referred to mitochondrial autophagy (alias mitophagy) is key for the
appropriate cellular actions in addition to health.
Earlier we had reviewed part of SIRTs in the form of epigenetic modifiers regarding
postponement of Diabetic Kidney Disease(DKD)& in placental growth in pregnancy besides
how resveratrol could be used in numerous chronic inflammatory diseases and Autoimmune
Diseases, Part of NLRP3 Inflammasome, Telomeres Dynamics in Reproduction, SIRT signaling
pathway the significance of SIRT signaling pathway with NAD metabolism regarding improving
oocyte quality, mitophagy part in treating HBsAg&PCOS.Detailed autophagy in Bile acid
metabolism in cancer &in diabetic cardiomyopathy&T1DM [11-21]. Numerous mitophagy
pathways implicate various signaling molecules, enzymes as well as adapter proteins. Here we
detail concisely with availability of considerable comprehensive reviews with regard to various
mitophagy pathways [22].
METHODS
Here we conducted a narrative review utilizing search engine pubmed,google scholar; web of
science; embase; Cochrane review library utilizing the MeSH terms like Sirtuins; maternal
ageing; Oxidative stress (OS); organs ageing; oocytes quality; natural mitophagy agents;
synthetic agents; mitochondria function; Epigenetics; DNA methylation; Histone deacetylation;
DNA healing; chromatin remodeling; cellular senescence; immunecell working ; melatonin;
resveratrol; astaxanthin; nicotinamide mononucleotide; urolithinA; nicotinamideriboside;
from 1985 to 2024 till date.
RESULTS
We found a total of 1000 articles out of which we selected 90 articles for this review. No meta- analysis was done.
PINK1/PARKIN Based Mitophagy
In healthy mitochondria phosphatase as well as tension homolog (PTEN) induced kinase
[PINK1] gets imported to the inner mitochondrial membrane (IMM), along with thereby
Page 3 of 20
30
British Journal of Healthcare and Medical Research (BJHMR) Vol 11, Issue 05, October-2024
Services for Science and Education – United Kingdom
targeted for breakdown by the presenilin associated rhomboid-like protein (PARL) as well as
the cytosolic proteasome. Nevertheless, once mitochondrial membrane potential (MMP)
diminishes, PINK1 accrual takes place at the outer mitochondrial membrane (OMM), in addition
to its activation takes place via autophosphorylation [23]. Phosphorylation of ubiquitin results
by PINK1 followed by enrollment of E3 ubiquitin ligase Parkin to the OMM [23,24].
Furthermore, it possesses the capacity of completely activating Parkin via direct
phosphorylation on the serine 65(in the ubiquitin like domain) whose escalation further takes
place on the binding of the Parkin to the phosphor- ubiquitin [25]. Parkin possess the capacity
of ubiquitination of numerous OMM proteins inclusive of voltage dependent anion channels
(VDAC), mitofusin 2(MFN2) as well as TANK binding kinase (TBK) [26]. Ubiquitinated OMM
proteins crosstalk with the cargo receptors for instance proteins that possess the capacity of
concurrently crosstalking with autophagosome correlated Atg8/ light chain 3B(LC3) family of
proteins in addition to ubiquitin [26] inclusive of optineurinin (OPTN) as well as nuclear dot
protein 52 (NDP52) [ 23,24]. (Figure1) [rev in ref 27].
Besides the detailed signaling pathways, the mitophagy modulated by PINK1/ Parkin might
implicate other mitophagy receptors for instance prohibitin2 IMM protein [28].
Legend for Figure 1.
Courtesy ref no-27-Schematic illustration of three mitophagy pathways (left to right, inspired
by [23]).
PINK1/Parkin-dependent mitophagy: The decrease in membrane potential in damaged
mitochondrial regions leads to the accumulation of PINK1 on the outer mitochondrial
membrane (OMM), where it recruits Parkin. PINK1 activates Parkin by phosphorylating it
within its ubiquitin-like domain, releasing its activity. Parkin then ubiquitinates OMM