Maternal Inheritance of Mitochondria: What Happens to Paternal Mitochondria?

Mitochondria（感謝Keith Porter/SPL提供）

Mitochondria are the organelles responsible for supplying energy that powers cellular metabolism in eukaryotic cells. They replicate during specific stages of the cell cycle and are distributed to daughter cells during cell division. Unlike most cellular structures, mitochondria contain their own circular DNA. In humans, mitochondrial DNA is approximately 16,000 base pairs in length and most of its genes are involved in oxidative phosphorylation, the process responsible for energy production. The existence of mitochondrial DNA provided strong support for the endosymbiotic theory proposed by Konstantin Mereschkowski in 1905, which suggested that mitochondria originated from symbiotic bacteria that once lived inside ancestral eukaryotic cells.

One intriguing feature of mitochondrial genetics is that mitochondria are typically inherited only from the mother. Although this maternal inheritance pattern is widely recognized, the fate of paternal mitochondria during reproduction remained unclear for a long time. Only in recent years have researchers begun to uncover the mechanisms that remove paternal mitochondria during or shortly after fertilization.

Maternal inheritance is not universal across all sexually reproducing species. In some organisms, mitochondria can be inherited from both parents. Examples include the Mediterranean mussel Mytilus galloprovincialis, the clam Ruditapes philippinarum, and cicadas of the genus Magicicada. In addition, about 6–15% of individuals of Drosophila simulans show biparental mitochondrial inheritance. Biparental inheritance is extremely rare in mammals, but a few human cases have been reported. One of the first documented examples involved a patient suffering from mitochondrial myopathy. The patient's mitochondrial DNA contained a two-base-pair deletion in the ND2 gene, which impaired the electron transport chain of cellular respiration. Genetic analysis revealed that the defective ND2 gene was inherited from the father's mitochondrial DNA, demonstrating that mitochondria from both parents were present in the patient's cells.

Another phenomenon that can produce apparent paternal mitochondrial inheritance involves nuclear mitochondrial sequences, commonly called NUMTs. In this situation, fragments of mitochondrial DNA become inserted into the nuclear genome through DNA recombination. These sequences can then be passed to the next generation as part of nuclear DNA. In some cases, the inserted fragments later return to mitochondria, which may create the appearance of biparental mitochondrial inheritance.

Recent research has shown that paternal mitochondria and their DNA can be actively eliminated both before and after fertilization. The mechanisms involved vary among species.

In sperm cells, mitochondria are usually concentrated in the tail, where they supply the energy required for motility. During fertilization in the Chinese hamster Cricetulus griseus, only the sperm head enters the egg, while the tail containing mitochondria remains outside. This situation prevents paternal mitochondria from entering the embryo. However, such a mechanism is relatively uncommon. In most species, the sperm tail does enter the egg cell, meaning paternal mitochondria are present in the fertilized egg for a short period. This transient presence has been observed in the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, mice, and humans. These species have therefore become important model systems for studying how paternal mitochondria are removed during early development.

The nematode Caenorhabditis elegans possesses two sexual forms: hermaphrodites and males. Hermaphrodites can reproduce by self-fertilization, while males can mate with hermaphrodites to increase genetic diversity. Approximately thirty minutes after sperm enters the egg, specialized vesicles called autophagosomes begin to form around paternal mitochondria and associated membranous organelles. Autophagosomes engulf these structures and subsequently fuse with lysosomes, cellular compartments that contain enzymes capable of degrading biological molecules. Through this process, paternal mitochondria are gradually dismantled.

As embryonic cell divisions proceed, paternal mitochondria continue to disappear. By the stage when the embryo has divided into eight to sixty-four cells, paternal mitochondria have largely been eliminated. When genes involved in autophagy are mutated, however, paternal mitochondria can persist until the larval stage. This observation demonstrates that autophagy is essential for their removal.

The fertilized egg must also distinguish paternal mitochondria from maternal ones. In C. elegans, paternal mitochondria contain a protein called CPS-6, which is normally associated with the outer mitochondrial membrane. After fertilization, CPS-6 moves into the mitochondrial matrix and contributes to the degradation of the inner membrane and the loss of membrane potential. As a result, paternal mitochondria become damaged organelles, marking them for removal through autophagy.

Fruit flies eliminate paternal mitochondrial DNA through a different strategy. During spermatogenesis in Drosophila melanogaster, mitochondria within the sperm tail fuse together to form two extremely long structures that run parallel to the tail. Inside these mitochondria, an enzyme called EndoG degrades mitochondrial DNA. By the time sperm mature, their mitochondria contain little or no DNA. This means paternal mitochondrial DNA has little chance of entering the fertilized egg.

After fertilization, the egg still removes the paternal mitochondria themselves. The long mitochondrial structures are fragmented into small pieces, which are then eliminated by autophagosomes and endosomes.

In mammals such as mice and humans, sperm mitochondria carry proteins that are already marked with ubiquitin molecules before fertilization. Ubiquitin acts as a molecular label indicating that a protein or organelle should be degraded. One candidate target of this labeling is a mitochondrial inner-membrane protein called prohibitin. Once sperm mitochondria enter the egg, the ubiquitin tags allow cellular degradation systems to recognize them. The ubiquitin–proteasome system and autophagy then cooperate to dismantle paternal mitochondria. By the morula stage of embryonic development, when the embryo consists of about thirty-two cells, paternal mitochondria can no longer be detected.

Another hypothesis proposes that paternal mitochondria disappear through passive dilution. According to this model, paternal mitochondria are not actively destroyed. Instead, they simply fail to replicate after entering the egg. As the embryo divides repeatedly, the number of maternal mitochondria increases while paternal mitochondria remain constant. Over time, the paternal mitochondria become so rare that they are effectively undetectable. Some studies in mice have indeed detected extremely small numbers of paternal mitochondria persisting for extended periods.

Despite this possibility, most researchers now agree that active degradation mechanisms are the primary reason paternal mitochondria disappear. The combined action of ubiquitin signaling, the proteasome, and autophagy provides strong evidence for targeted elimination.

Why evolution favors maternal mitochondrial inheritance remains an open question. One explanation involves the vulnerability of mitochondrial DNA to damage. Mitochondria produce reactive oxygen species during metabolism, and these molecules can damage mitochondrial DNA. Because mitochondrial DNA lacks many protective features present in nuclear DNA, it accumulates mutations more easily. In addition, the environment in which sperm develop and are stored exposes mitochondrial DNA to elevated risks of damage.

Maintaining a single maternal source of mitochondria may therefore reduce the likelihood that harmful mutations are passed to offspring. Studies in mice have shown that individuals with heteroplasmy—cells containing mitochondria from more than one source—can develop abnormalities in behavior and metabolism, including reduced activity and impaired cognitive function. Eliminating paternal mitochondria thus helps maintain the genetic stability of mitochondrial populations in developing embryos and prevents the inheritance of mitochondrial disorders.

Author: Shui-Ye You

Reference:

1. Ken Sato, Miyuki Sato. Multiple ways to prevent transmission of paternal mitochondrial DNA for maternal inheritance in animals. J Biochem. 2017 Oct 1;162(4):247-253.

2. Karla Pacheco de Melo, Mariana Camargo. Mechanisms for sperm mitochondrial removal in embryos. Biochim Biophys Acta Mol Cell Res . 2021 Feb;1868(2):118916.

3. Taeko Sasaki, Miyuki Sato. Degradation of paternal mitochondria via mitophagy. Biochim Biophys Acta Gen Subj. 2021 Jun;1865(6):129886.