Mitochondrial matters: Mitochondrial bottlenecks, self-assembling structures, and entrapment in the female germline

Abstract

Mitochondrial replacement therapy, a procedure to generate embryos with the nuclear genome of a donor mother and the healthy mitochondria of a recipient egg, has recently emerged as a promising strategy to prevent transmission of devastating mitochondrial DNA diseases and infertility. The procedure may produce an embryo that is free of diseased mitochondria. A recent study addresses important fundamental questions about the mechanisms underlying maternal inheritance and translational questions regarding the transgenerational effectiveness of this promising therapeutic strategy. This review considers recent advances in our understanding of maternal inheritance of mitochondria, implications for fertility and mitochondrial disease, and potential roles for the Balbiani body, an ancient oocyte structure, in mitochondrial selection in oocytes, with emphasis on therapies to remedy mitochondrial disorders.

Selection of mitochondria in female germline cells: is Balbiani body implicated in this process?

“…1 b). These observations have led to an assumption that only high membrane potential mitochondria are recruited to the Bb [ 3 , 8 ] and that mitochondria with lowered membrane potential (i.e., overloaded with mutations in mtDNA) are excluded from the Bb and subsequently eliminated by mitophagy [ 9 ]. Thus, only the most fit and active mitochondria are transmitted to the next generation [ 3 , 4 , 8 , 53 ].…”

“…The involvement of the Bb in the selection of the mitochondria in developing oocytes has been already suggested [ 3 , 8 , 9 ]. Critical review of all available data supports this idea and points out that the Bb might be an important player in the bottleneck phenomenon.…”

“…Several lines of evidence suggest that mitochondria overloaded with mutations in mtDNA are selectively eliminated from the growing oocytes [ 1 – 4 ]. Although, the mechanism of this purifying selection is far from being understood, it is widely accepted that it relies on the mtDNA bottleneck phenomenon [ 5 – 8 ], which involves an expansion of healthy mitochondria within the oocyte cytoplasm (ooplasm), selective directional transport of mitochondria to the germ plasm (located at the vegetal cortex in frogs and the posterior oocyte pole in holometabolous insects), and elimination of dysfunctional mitochondria by apoptosis of oocytes with excessive deleterious mtDNA mutations [ 1 , 2 , 4 ]. It has recently been proposed that the selection of mitochondria in developing oocytes is related to the formation and dispersion of the Balbiani body [ 3 , 8 , 9 ].…”

The Role of Mitochondria in Oocyte and Early Embryo Health

“…The pre-fertilization bottleneck occurs during oogenesis, where the number of mitochondria in the germline is severely reduced before maturation of the oocyte. The post-fertilization bottleneck occurs between the zygote formation and the blastocyst stage, during which there is intense cell division but suppression of mitochondrial proliferation, a mechanism that leads to a reduced number of mitochondria per cell [5,[42][43][44].…”

Możliwości przywracania i utrzymania jakości mitochondriów w oocytach ssaków

“…Wiadomo, że mutacje mitochondrialne negatywnie wpływają na płodność i mogą przyczyniać się do utraty rezerwy jajnikowej i przedwczesnej menopauzy (wanG i sun 2007). Przypuszcza się, że linia komórek płciowych ma mechanizmy pozwalające na ograniczenie liczby mutacji w obrębie genomu mitochondrialnego przekazywanego potomstwu, które jednak nie są w stanie wyeliminować wszystkich nieprawidłowości (Marlow 2017). Dla polepszenia płodności człowieka poszukuje się sposobów wspomagania pracy mitochondriów lub usuwania zmutowanych kopii mtDNA z linii płciowej.…”