What Happens When the Cell’s Powerhouse Fails? Understanding Mitochondrial Dysfunction

Mitochondria, often referred to as the ‘powerhouse of the cell,’ play a pivotal role in converting the food we consume into the essential fuel, ATP (adenosine triphosphate), required for our body’s vital functions. These cellular structures not only produce energy but also serve various critical roles within the cell. In fact, approximately 90% of the body’s energy requirements are met through mitochondrial activity[1]. 

However, disturbances like genetic mutations, diseases, or even dietary factors can disrupt mitochondrial function, leading to what we term as ‘mitochondrial dysfunction.’ This malfunctioning process, when accelerated, can severely affect specific organs, especially those with high energy demands, such as muscles, brain, and the heart. Importantly, dysfunctional mitochondria are implicated in conditions like Alzheimer’s and Parkinson’s diseases[2]. 

  Mitochondrial disease clinical symptoms. 

Primary mitochondrial diseases (PMD) constitute a rare inherited group, characterized by the inability of malfunctioning mitochondria to meet the cell’s energy needs. These diseases progressively impact multiple organ systems, representing a wide clinical and genetic spectrum. Affecting approximately 1 in 5000 individuals, PMD stands as one of the most prevalent rare diseases[3]


Human mitochondrial DNA. Unlike nuclear DNA, mitochondrial DNA is a small, circular, double-stranded molecule, and it is around 16.5kb long
(Amorim et al., 2019)

The genetic basis of mitochondrial diseases is multifaceted. Mitochondria possess their own unique genetic material, distinct from the cell nucleus, solely inherited from the mother. However, this mitochondrial genetic material, comprising only 37 genes, is insufficient for mitochondrial function[4]. About 99% of the necessary genes for functional mitochondria are encoded by nuclear DNA (nDNA) located in the cell nucleus. Mutations in these genes, found in roughly 75-90% of individuals with mitochondrial disease, are spread across different chromosomes, including the X chromosome. Despite various mutations causing similar clinical symptoms, the same mutation may lead to diverse phenotypes[5]

Presently, treatment options for mitochondrial diseases predominantly involve supportive measures aimed at alleviating symptoms, as definitive treatment methods are yet to be established. However, ongoing research into the mechanisms underlying these diseases and potential therapeutic elements has gained momentum and disease-modifying drugs are under investigation. 

Notably, Khondrion, a clinical-stage biopharmaceutical company, has made significant strides in advancing its lead drug candidate, sonlicromanol (also known as KH176) [6]. Sonlicromanol has shown promise in preclinical studies by scavenging reactive oxygen species, acting as a redox modulator , and by inhibiting mPGES-1[7]. Encouraging results from Phase-I and Phase-II studies in patients with the m.3242A>G mutation in the mtDNA-encoded tRNALeu (UUR) gene have supported the progression to Phase-III studies as announced by Prof. Dr. Jan Smeitink, Chief Executive Officer of Khondrion[8]

Furthermore, investigations into the therapeutic effects of NAD repletion in PMD models using Khondrion compounds and NAD precursor supplements, like DC8 in the NADis consortium, represent exciting avenues of exploration.  

Stay tuned for further developments! 

Author: Melisa Emel Ermert

[1] David C CHAN, “Mitochondria: dynamic organelles in disease, aging, and development,” Cell, vol. 125, no. 7, pp. 1241–52, 2006. 

[2] Holper, L., Ben-Shachar, D. & Mann, J. Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease. Neuropsychopharmacol. 44, 837–849 (2019). https://doi.org/10.1038/s41386-018-0090-0 

[3] R. K. Naviaux, “Developing a systematic approach to the diagnosis and classification of mitochondrial disease,” Mitochondrion, vol. 4, pp. 351–361, 2004. 

[4] J.-W. Taanman, “The mitochondrial genome: structure, transcription, translation and replication,” Biochim. Biophys. Acta – Bioenerg., vol. 1410, no. 2, pp. 103–123, 1999. 

[5] D. M. Turnbull and P. Rustin, “Genetic and biochemical intricacy shapes mitochondrial cytopathies,” Neurobiol. Dis., 2015. 

[6] https://www.khondrion.com/our-science/ 

[7] Beyrath, J., Pellegrini, M., Renkema, H. et al. KH176 Safeguards Mitochondrial Diseased Cells from Redox Stress-Induced Cell Death by Interacting with the Thioredoxin System/Peroxiredoxin Enzyme Machinery. Sci Rep 8, 6577 (2018). https://doi.org/10.1038/s41598-018-24900-3 

[8] https://www.khondrion.com/khondrion-announces-sonlicromanol-phase-iib-progress-supporting-phase-iii-development-in-melas-spectrum-disorders/ 

*The document was edited and grammar-checked for clarity with assistance from ChatGPT 






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