Mitochondria in Metabolic Syndrome, Reproduction and Transgenerational Inheritance—Ongoing Debates and Emerging Links

Mitochondria play important roles in energy production, biosynthesis, reactive oxygen species (ROS), calcium homeostasis, and cell signaling. Damage to mitochondria is commonly caused by defects in oxidative phosphorylation, decreases in mitochondrial number and activity, mutations in mitochondrial DNA (mtDNA), and ROS production. These defects have been shown to occur in a broad range of pathological conditions such as insulin resistance (IR), diabetes, heart disease, cancer, and reproductive disease. Accordingly, dysfunctional mitochondria have been associated with many metabolic disorders. However, whether mitochondrial dysfunction is a cause or effect of these pathobiologies has in many cases been difficult to determine. A recent publication by Das et al (2020) highlights this issue by discussing the potential mechanisms underlying mitochondrial dysfunction and its association with IR, diabetes, and reproductive abnormalities (1).

Despite the obvious functions of mitochondria in cellular metabolism, the exact role of mitochondrial dysfunction in driving systemic metabolic disorders remains an open debate. There are variable reports on the causal relationship between mitochondrial dysfunction and IR with type 2 diabetes mellitus (T2DM). Correlative studies suggest functional abnormalities of mitochondria in skeletal muscle biopsies from patients with IR and T2DM (2, 3). In contrast, diabetic, obese, and IR individuals with normal, decreased, or compensatory increases in mitochondrial activity in skeletal muscle have been documented, suggesting mitochondrial function in muscle alone cannot predict metabolic syndrome. Preclinically, muscle-specific damage to mitochondrial functions did not cause IR (4). Part of the problem with linking mitochondrial functions to biology may be due to differences in how mitochondrial fitness is defined—some groups define mitochondrial dysfunction as decreased mitochondrial activity and oxidative phosphorylation, others focus on mitochondrial numbers, and yet others equate mitochondrial fitness to ROS levels. This area would benefit greatly from a universally accepted definition of mitochondrial dysfunction in addition to more rigorously controlled epidemiological studies that better define disease states (i.e., pre-, early, and late diabetes) and consider sex/hormonal differences. Preclinical studies leveraging new conditional genetic mouse models and methodological approaches that facilitate deeper metabolic insights such as stable isotope tracing and mitochondrial membrane potential assessment would provide a more uniform functional characterization of mitochondria and help parse out cause and effect.

Although the debate over the role of mitochondria in metabolic syndrome rages on, emerging evidence indicates a causative link between mitochondrial dysfunction, reproductive abnormalities, and metabolic diseases in offspring. Women with gestational diabetes mellitus exhibit reduced placental mitochondria, impaired placental development, and an increased risk of developing T2DM later in life. Given that mitochondria are inherited from the mother, it is perhaps not surprising that the offspring of women with gestational diabetes mellitus are also at an increased risk for developing T2DM (5). In mice, diet-induced obesity in mothers predicted metabolic syndrome associated with mitochondrial dysfunction in muscle that was passed through females to the next 3 generations of offspring, all fed a control diet (6). Although these findings provide a plausible mechanism for transmission of metabolic dysfunction through the female germline, it is still unclear whether altered mitochondria can be passed from mother to child through the oocyte to cause later metabolic syndrome directly or whether this is the indirect result of a stressful environment created in the placenta.

Further pointing to key roles for mitochondria in ovarian function, mitochondrial copy number is commonly used to assess embryos during in vitro fertilization. Importantly, the age-related decline in female fertility is associated with mitochondrial dysfunction (7). This is highly significant given that many women wait to have children until their late 30s and beyond. Understanding what causes the age-related decrease in fertility is necessary for the development of new approaches to improve ovarian functions and subsequent fertility. Of note, oogenesis results in a ~ 10 000-fold increase in mitochondria during the journey from primordial germ cell to mature oocyte. Although most oocyte mitochondria are inactive until the blastocyst stage, the increased ROS that results from mitochondrial dysfunction early may augment premature aging. Hence, any dysregulation of mitochondria in early oogenesis could be magnified during development. As such, quality may be far more important than quantity with regard to mitochondria in oocyte and blastocyst development. In that regard, increased mtDNA content could be a feedback mechanism when the cell senses damaged mitochondria. The link between mitochondrial fitness and ovarian function is supported by the observation that women with polycystic ovarian syndrome (PCOS) or primary ovarian insufficiency have increased mitochondrial dysfunction. These data are consistent with the observation that 40% of infertile women undergoing in vitro fertilization had mtDNA mutations in oocytes and blastocysts. Importantly, oocytes with mtDNA mutations had low fertilization rates (8). These studies have been supported in preclinical models of mtDNA instability.

Beyond the germ cells, mitochondria also have important functions in the granulosa cells that support oocyte development. Women with PCOS or primary ovarian insufficiency accumulate ROS within the intrafollicular microenvironment and in granulosa cells. The higher levels of ROS in granulosa cells have been linked to decreased fertility in women with PCOS. Moreover, dysfunctional mitochondria may also disrupt the normal steroidogenesis in granulosa cells needed to support follicular development. Whether the reverse is true, that alterations in sex steroid levels can impair mitochondrial function, remains to be determined. Taken together, optimal mitochondrial function is necessary for ovarian reserve maintenance and preservation of oocyte quality.

Given the importance of mitochondria in ovarian biology, therapeutic strategies have been proposed to improve mitochondrial function. Preclinical studies highlighted that coenzyme Q10, sirtuin-1 activators, nitric oxide, and antioxidant cocktails could improve fertility. Clinically, transfer of functional mitochondria or cytoplasm from donor oocytes into dysfunctional oocytes has had success restoring mitochondrial function and enabling the successful delivery of healthy babies. However, this approach has the potential limitation of increased heteroplasmy and warrants further studies. Conversely, the use of autologous transfers, although preventing heteroplasmy, are yet to yield clear benefit in humans. These issues provide the impetus for the development of new approaches to prevent transgenerational mitochondrial dysfunction and highlight the need to address both how and when to treat patients to limit transmission to their offspring.

Glossary

Abbreviations

IR

insulin resistance

mtDNA

mitochondrial DNA

PCOS

polycystic ovarian syndrome

ROS

reactive oxygen species

T2DM

type 2 diabetes mellitus

Additional Information

Disclosure Summary: D.E.F. has received research funding from GTx, Inc, and has a familial relationship with Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals, and Barricade Therapeutics. E.S. reports no potential conflicts of interest.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.