Ginkgolic Acids Impair Mitochondrial Function by Decreasing Mitochondrial Biogenesis and Promoting FUNDC1-Dependent Mitophagy

Abstract

Ginkgolic acids (GAs) are found in the leaves, nuts, and testa of Ginkgo biloba and have been reported to exhibit antitumor, antibacterial, and pro-apoptotic activities. However, their role in mitochondrial function is still unclear. Our previous study showed that genes related to the mitochondria present significant changes in GA-treated mouse bone marrow stromal cells. We hypothesize that GAs may regulate mitochondrial function. Here, we found that GA treatment induced mitochondrial fragmentation, reduced mtDNA copy numbers and mitochondrial protein levels, and impaired mitochondrial adenosine 5′-triphosphate production and oxygen consumption. The GA-induced mitochondrial mass loss may be due to decreased mitochondrial biogenesis. In addition, abolishing autophagy by Atg7 knockout or the administration of an autophagy inhibitor can restore the GA-induced decrease in mitochondrial mass. Furthermore, FUNDC1 knockdown restored the GA-induced changes in mitochondrial mass reduction and mitochondrial membrane potential loss. Together, our studies demonstrated that GAs impaired mitochondrial function by decreasing mitochondrial biogenesis and promoting FUNDC1dependent mitophagy.

Mitophagy in Human Diseases

“…The vast majority of available data comes from preclinical studies. Natural compounds, such as pomegranate and Ginkgo biloba extracts, or chemical compounds modulators of mitophagy have been tested mainly in vitro [ 412 , 413 , 414 ]. A new type of molecule initially developed for cancer treatment is attracting significant scientific interest as a promising mitophagy therapeutical tool, the so-called selective, ubiquitin-mediated “autophagy targeting chimera” (AUTAC) [ 415 ], which is able to potentiate mitochondrial turnover and facilitate the removal fragmented mitochondria in vitro in fibroblasts [ 416 ].…”

A Balanced Act: The Effects of GH–GHR–IGF1 Axis on Mitochondrial Function

“…Like ancient Chinese philosophy “Ying” and “Yang,” both generation of newly synthesized mitochondria, by mitochondrial biogenesis, and elimination of detrimental and/or superfluous mitochondria, by mitophagy, are predominantly required for maintaining mitochondrial homeostasis. Recent findings have hinted that any abnormality in these two opposing processes can influence the quantity and quality of mitochondria, which will further affect mitochondrial function and the ability of cells to adjust their mitochondrial networks in response to physiological adaptations and stress conditions ( Palikaras et al, 2015 ; Singh et al, 2018 ; Wang et al, 2019 ; Yau et al, 2019 ; Zhou et al, 2019 ; Chen et al, 2020 ). At the same time, impaired mitochondrial function and homeostasis are now widely accepted to be associated with multiple aspects of the aging process and age-onset diseases ( Lopez-Otin et al, 2013 ; Mattson and Arumugam, 2018 ; Akbari et al, 2019 ).…”

Puerarin Inhibits FUNDC1-mediated Mitochondrial Autophagy and CSE-induced Apoptosis of Human Bronchial Epithelial Cells by Activating the PI3K/AKT/MTOR Signaling Pathway

“…FUNDC1 is localized on the outer mitochondrial membrane and participates in mitochondrial autophagy caused by hypoxia and reduced mitochondrial membrane potential, in which the phosphorylated form of FUNDC1 inhibits autophagy while dephosphorylation promotes autophagy [20,21]. Wang et al found that mitochondrial DNA copy number and mitochondrial protein expression were signi cantly decreased in Ginkgolic acids-treated mouse bone marrow stromal cells, but FUNDC1 gene knockout restored Ginkgolic acids-induced changes in mitochondrial mass loss and mitochondrial membrane potential loss [22]. Another study showed that FUNDC1 plays an important regulatory role in hypoxia-induced PC12 neuroautophagy and apoptosis, and overexpression of FUNDC1 can promote autophagy and then prevent neuronal apoptosis [20].…”