[www.ncbi.nlm.nih.gov]

In this study, pomegranate extract (PE) supplementation is shown to stimulate mitophagy. PE activates transcription factor EB (TFE to upregulate the expression of autophagy and lysosomal genes for mitochondrial quality control under basal and stress conditions.

Autophagy dysregulation is a feature commonly observed in aging and age-related disorders like neurodegeneration39,40. The critical role of TFEB as a master regulator of genes involved in the lysosomal–autophagic pathways makes it an attractive therapeutic target for human diseases associated with autophagy or lysosomal dysfunction. Indeed, an increasing number of studies have demonstrated the potential of TFEB induction in mitigating lysosomal storage disorders41–44 and proteinopathies45–49. In addition, TFEB activation is associated with healthy lifespan and longevity50,51. Therefore, molecules or compounds that can activate TFEB hold promise as interventions to delay the onset or progression of aging and diseases.

Currently known TFEB activators involve stress triggers such as starvation and mitochondrial stress, as well as mTOR inhibitors52. However, mTOR regulates numerous cellular processes and inhibition of the kinase is likely to elicit a plethora of undesirable side effects53.

TFEB participates in a myriad of cellular processes13. In this study, PE upregulates TFEB-induced autophagy for mitochondrial quality control. Under basal condition, PE distinctively influences basal tubular mitochondrial network and encourages formation of “donut-shaped” mitochondria (Fig. 4a,b). Understanding of the significance of “donut-shaped” mitochondria is currently limited. Studies have proposed that the “donut” shape is an intermediate configuration between tubular shape and mitochondrial fragmentation56. Spherical mitochondria are observed to form rapidly and transiently during the early response to mitochondrial depolarization in a fission-independent way57,58. The “donut” mitochondria either derived from mitochondrial membrane bending around cytoplasmic constituents or from the invagination of mitochondrial membrane to form a cavity to pull in cytoplasm57,58

We postulate that PE-mediated intracellular Ca2+ changes may bring about mitochondrial membrane potential changes or curvature to form spherical mitochondria. Further, PE enhances the recruitment of the autophagosomes to the “donut” mitochondria basally during the structural transformation to form the spherical mitochondria (Fig. 4c).

Mitophagy is a key determinant of longevity where it protects against age-dependent accruement of deleterious mitochondria to reduce futile ATP hydrolysis, ROS production, pro-inflammatory responses and mutated mitochondrial DNA burden63–66. Defects in mitophagy have also been observed in pathologies such as cancer, metabolic syndrome and neurodegeneration3,4,64,67. Hence, PE-induced mitophagy poses as a viable way to improve mitochondrial health and to prolong lifespan and prevent age-related pathologies. In support of this, urolithin A, a metabolite of PE-associated polyphenol ellagitannins, induces mitophagy and extends healthspan and lifespan in C. elegans12. Urolithin A-induced mitophagy was also recapitulated in mammalian muscle and intestinal cells, which is shown to improve muscle functions in rodents by preventing age-related accumulation of dysfunctional mitochondria and decline in metabolic bioenergetics12. Similar to PE, urolithin A also alters mitochondrial morphology12. Although the mechanism that underpins urolithin A-induced mitophagy remains obscure, our study strongly suggests TFEB as a mediator of urolithin A and PE-induced mitophagy.

Taken together, activation of TFEB by PE positively influences mitochondrial health. Hence, PE supplementation represents a potential therapeutic strategy for mitochondrial-related diseases.

pomegranate extract (PE) supplementation is not very useful to raw foodists.
They are cooked, processed, and void of life.

A more useful study will be to find out what benefits are there to eating raw pomegranates and where to find the most useful nutrients.

In the juice?
In the seed?
In the pulp?

You make a good point.