Introduction

Mitochondria produce cellular energy in the form of adenosine triphosphate (ATP). Within the double-layered mitochondrial membrane, the series of four protein complexes (Complexes I through IV) known as the respiratory or electron transport chain, create a biochemical cascade leading to the generation of ATP through a fifth complex (Complex V, also known as ATP synthase) that extends into the mitochondrial cytoplasm. Complex deficiencies can occur anywhere along the chain, and a deficiency in one complex will create downstream dysfunction. All five complexes are encoded for and by both the mitochondrial and nuclear genomes. Genetic coding errors can lead to depletion in the number of mitochondrial DNA (mtDNA) and reduction in ATP synthesis.

When considering disease processes that result from mitochondrial dysfunction, it is necessary to understand the impact of nuclear DNA (nDNA) on the role of mitochondria. Mitochondria are controlled by the coordination of both the mtDNA and nDNA genomes. Previous articles in this column have focused on the mtDNA genome, and mutations and deletions within that are associated with disease entities. The mitochondrial genome is circular in shape and made up of 16,569 mtDNA base pairs and 37 genes. By comparison, the nDNA genome contains approximately 3 million base pairs and about 20,000 genes within its 23 pairs of chromosomes. While mtDNA is replicated, transcribed, processed, and translated within the mitochondrion, almost all the proteins required for these processes are encoded in the nDNA genome (Stenton & Prokisch, 2020). nDNA affects mitochondrial complex assembly, biogenesis, mtDNA replication and transcription, and protein biosynthesis. Dysfunction in any of these areas can lead to multisystemic disease processes.

Nuclear DNA and the mitochondria

The nDNA disorders are inherited in Mendelian patterns, including autosomal dominant, autosomal recessive, and X-linked inheritance. This differs from mtDNA disorders, which are most commonly maternally inherited. nDNA pathogenic variants associated with primary mitochondrial disorders, particularly childhood-onset disorders, are commonly inherited in an autosomal recessive manner (McCormick et al., 2018). There are nuclear genes that encode proteins involved in mtDNA replication (including POLG, TWNK, SSBP1, and PRIMPOL), transcription of mtDNA (including TFAM and POLRMT), mitochondrial fusion, fission, and mobility (including OPA1, MFN1, and MFN2), nucleotide metabolism (including TK2 and DGUOK), and other functions (Rusecka et al., 2018). This article focuses on mutations in two specific nuclear genes, POLG and OPA1, and describes the impact of these nDNA changes on mitochondrial function.

POLG-related disorders

The nuclear gene polymerase γ (also referred to as polymerase gamma or POLG) is located on the long arm of chromosome 15. The POLG gene encodes for DNA polymerase γ, an essential enzyme involved in mtDNA replication and repair. With approximately 300 known pathogenic gene variants, POLG mutations are the most common cause of inherited mitochondrial disease and the most frequent cause of mitochondrial epilepsy (Russo et al., 2022; Rahman & Copeland, 2018). The phenotype includes neurologic, eye, and cardiac disorders. Neurologic disorders include central nervous system disorders such as developmental delay, encephalopathy, seizures, psychomotor regression, stroke-like episodes, and peripheral neuropathy as well as peripheral nervous system conditions such as ataxia, chorea, and parkinsonism, hypotonia, myopathy, weakness, and fatigue. Eye symptoms include ptosis and external ophthalmoplegia, which is eye muscle weakness and paralysis. Cardiomyopathy and endocrinopathies such as diabetes mellitus also occur. Disease entities associated with POLG mutations include progressive external ophthalmoplegia, ataxia neuropathy spectrum, myoclonic epilepsy myopathy sensory ataxia, and childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life (Rahman & Copeland, 2018). Leigh syndrome (previously described by Heuer & Seibert, 2022) is also associated with POLG mutations.

A severe POLG-related disorder, Alpers (or Alpers-Huttenlocher) syndrome, occurs when a mutation in POLG replaces the amino acid alanine with the amino acid threonine at position 467 (written as Ala467Thr or A467T) (MedlinePlus.gov, n.d.). This causes mtDNA depletion and a decrease in cellular energy, affecting tissues whose cells do not divide continually, such as the brain, muscle, and liver. Alpers syndrome is often noted in early childhood, although the affected child can initially develop normally for the first months or years of life. The syndrome is characterized by a clinical triad of symptoms: refractory seizures, often with a focal component; psychomotor regression that may be episodic and triggered by intercurrent infection; and hepatopathy with or without acute liver failure (Jha et al., 2022). Because Alpers syndrome often presents with generalized seizures including status epilepticus (SE), clinicians may initially consider prescribing valproate, one of the mainstays of SE treatment. It is important to realize that valproate is contraindicated in children with POLG mutations because they cannot metabolize this drug, and fulminant hepatopathy with rapid progression to end-stage liver failure may occur. It is imperative to avoid valproate until a POLG mutation has been ruled out.

Treatment for Alpers syndrome is supportive, and life expectancy for youth with Alpers syndrome can range from a few months after diagnosis to more than a decade. Genetic diagnostic epilepsy panels include POLG mutations, but providers do not typically order these panels until a patient has presented with a first seizure episode.

OPA1-related disorders

Inherited mutations in the OPA-1 gene, located on the long arm of chromosome 3 (q28-q29), are associated with impaired mitochondrial fusion and alterations of the mitochondrial inner and outer membranes. The inner mitochondrial membrane is made up of folds (cristae) that increase the surface area of the inner membrane, thus increasing energy generation. Any decrease in membrane integrity reduces the mitochondria's ability to generate ATP. Among its many functions, OPA-1 regulates aspects of cellular respiration, mtDNA maintenance, cellular apoptosis, and calcium homeostasis. OPA-1 mutations are responsible for approximately 70% of all cases of autosomal dominant optic atrophy (Lenaers et al., 2021). Clinical features of this disease include progressive bilateral vision loss and color vision defects, sometimes specific to the blue–yellow spectrum. Patients experience a prominent loss of retinal ganglion cells and a reduction of the retinal nerve fiber layer thickness, and many patients develop legal blindness. Approximately 20% of patients with OPA-1 mutations have multisystemic disease manifestations which include ataxia, encephalopathy, sensorineural hearing loss, chronic progressive external ophthalmoplegia, peripheral neuropathy, and myopathy.

Researchers are exploring OPA-1 gene therapy treatment options designed to protect the integrity of retinal cells. In addition, potent antioxidants such as coenzyme Q-10 (ubiquinol dosing of 2–8 mg/kg/day in pediatric patients and 50–600 mg/day in adults, divided two or three times per day) and niacin (10 mg/kg/day divided two or three times per day), along with supplementation with the amino acid taurine, can support function of the respiratory chain and reduce reactive oxidative species that cause cellular damage.

Conclusion

The nDNA genome significantly affects mitochondrial function, and nDNA mutations are known culprits for causing mitochondrial disease. Both mtDNA genome sequencing and whole (nDNA) exome sequencing are essential when evaluating for suspected disorders of energy metabolism. While there are no current cures for mitochondrial disorders, accurate diagnosis can help the nurse practitioner clinician to identify these disorders, look for genomic underpinning, and help guide treatment options.

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