Endocrine Manifestations and New Developments in Mitochondrial Disease

Abstract

Mitochondrial diseases are a group of common inherited diseases causing disruption of oxidative phosphorylation. Some patients with mitochondrial disease have endocrine manifestations, with diabetes mellitus being predominant but also include hypogonadism, hypoadrenalism, and hypoparathyroidism. There have been major developments in mitochondrial disease over the past decade that have major implications for all patients. The collection of large cohorts of patients has better defined the phenotype of mitochondrial diseases and the majority of patients with endocrine abnormalities have involvement of several other systems. This means that patients with mitochondrial disease and endocrine manifestations need specialist follow-up because some of the other manifestations, such as stroke-like episodes and cardiomyopathy, are potentially life threatening. Also, the development and follow-up of large cohorts of patients means that there are clinical guidelines for the management of patients with mitochondrial disease. There is also considerable research activity to identify novel therapies for the treatment of mitochondrial disease. The revolution in genetics, with the introduction of next-generation sequencing, has made genetic testing more available and establishing a precise genetic diagnosis is important because it will affect the risk for involvement for different organ systems. Establishing a genetic diagnosis is also crucial because important reproductive options have been developed that will prevent the transmission of mitochondrial disease because of mitochondrial DNA variants to the next generation.

Keywords: MIDD; clinical management; diabetes mellitus; genomic testing; mitochondrial DNA; reproductive options.

Graphical Abstract

Figure 1.

Mitochondrial oxidative phosphorylation (OXPHOS) system and other pathways that are commonly implicated in mitochondrial diseases. The OXPHOS system comprises complexes I to V and 2 mobile electron carriers, CoQ₁₀ and cytochrome c. The breakdown of carbohydrate (glycolysis) and fatty acids (beta oxidation) lead to the production of acetyl-coenzyme A (CoA), which is the first substrate of the TCA cycle (also known as the citric acid cycle or Krebs cycle). NADH and FADH₂ are generated through a series of enzymatic reactions in which electrons are transferred along the mitochondrial respiratory chain (complex I-IV). High-energy electrons are passed along the complexes and protons (H⁺) are pumped out of the matrix space, creating an electrochemical membrane potential that is used by the ATP synthase (complex V) to phosphorylate ADP and generate ATP. The mtDNA encodes 13 protein subunits, 22 tRNAs and 2 rRNAs; there are multiple copies of mtDNA per cell, ranging from hundreds to thousands depending on the cell type. The replication, maintenance, transcription, and translation of mtDNA and mtDNA-encoded proteins are dependent on many nuclear-encoded proteins that are synthesized in the cytosol and imported into mitochondria through specific transporters (not shown). Genetic defects in nucleotide synthesis and salvage (eg, DGUOK, TYMP, TK2), mtDNA replication and maintenance (eg, catalytic subunit [POLG] and accessory units [POLG2] of polymerase gamma and TWNK), fusion and fission machinery (eg, MFN2, OPA1) can perturb mtDNA integrity and copy number, leading to the formation of multiple deletions and mtDNA depletion, respectively. This figure is derived from a previous published work (1).

Figure 2.

Multisystem manifestations of the m.3243-A > G-related mitochondrial disease. (A) Neurological. (i) Axial cranial MRI shows stroke-like lesions involving both occipital lobes with restricted diffusion. (ii) MRI sagittal view shows cerebellar and occipital lobe atrophy. (B) Ophthalmological. (i) Bilateral eyelid ptosis, reduced horizontal eye movement (ophthalmoplegia) and overactive frontalis muscles. (ii) Retinal picture shows macular dystrophy. (C) Audiological. Audiogram reveals a moderate to severe hearing loss that is more severe in the high-frequency range. (D) The position within the variable DHU loop of mt-tRNA^Leu(UUR) where the A > G substitution occurs. (E) Cardiac. A 12-lead ECG showing short PR interval (Wolff-Parkinson-White syndrome) and increased LV voltage compatible with LVH with repolarization abnormality. (F) Muscle. A skeletal muscle biopsy demonstrating COX-deficient muscle fibers (blue fibers). (G) Gut. Abdominal radiography showing severe dilated large bowel without evidence of mechanical blockade, consistent with intestinal pseudo-obstruction. (H) Renal. (i) Focal segmental glomerulosclerosis, tubulopathy, and chronic kidney disease are recognized associations with the m.3243A > G variant, independent of the diabetic status. (ii) Lower urinary tract dysfunction such as detrusor overactivity, bladder outlet obstruction, and stress incontinence has been reported. COX, cytochrome c oxidase; ECG, electrocardiogram; LV, left ventricular; LVH, left ventricular hypertrophy; MRI, magnetic resonance imaging.

Figure 3.

Proposed diagnostic algorithm for mitochondrial diabetes. LRPCR, long-range PCR; SNHL, sensorineural hearing loss.

Figure 4.

Proposed management algorithm of mitochondrial diabetes. BG, blood glucose; DPP4, dipeptidyl peptidase-4; GLP1, glucagon-like peptide 1; SGLT2, sodium-glucose transport protein 2; Su, sulphonylurea.

Figure 5.

Emerging treatment strategies for mitochondrial diseases. Repurposed and novel small molecules targeting different mitochondrial pathways (mitochondrial biogenesis, cardiolipin stabilizer, NAD⁺/NADH modulator, redox modulator/antioxidant) are classified as generic treatment approaches that have the potential to translate across different types of mitochondrial disease. On the other hand, specific treatment approaches such as allotopic gene therapy for LHON, nucleoside bypass therapy for mtDNA depletion syndrome, and methods of eliminating pathogenic mtDNA variants are examples of precision medicine in the mitochondrial field. Created with BioRender.com.

Figure 6.

Mitochondrial DNA transmission. Homoplasmic variants are transmitted from mother to offspring. The mitochondrial bottleneck explains how there can be extreme divergence in the heteroplasmy between mother and offspring. There is a genetic bottleneck during development that results in different heteroplasmy in each individual oocyte. This is a major challenge when providing genetic counselling for mothers with heteroplasmic mtDNA variants because the level of heteroplasmy will determine the clinical outcome in the offspring. This figure is derived from a previous published work (1) and created with BioRender.com.

Figure 7.

Mitochondrial replacement therapies. (A) Metaphase II transfer. (B) Pronuclei transfer. (A) Metaphase II transfer involves removing the metaphase II spindle from the donor oocyte and then transferring the metaphase II spindle from the patient carrying the pathogenic mtDNA variant. The oocyte is subsequently fertilized by the partner’s sperm. (B) Pronuclear transfer involves transferring the pronuclei, formed immediately after fertilization, from the mother’s oocyte into the enucleated oocyte of the donor woman. Both metaphase II spindle transfer and pronuclear transfer result in the nuclear DNA from both parents with the mitochondria (and mtDNA) from the donor woman. This figure is modified from a previous published work (197) and created with BioRender.com.