Mitochondria in Ageing and Diseases: The Super Trouper of the Cell

The past decade has witnessed an explosion of knowledge regarding how mitochondrial dysfunction may translate into ageing and disease phenotypes, as well as how it is modulated by genetic and lifestyle factors.[...].

Summary of papers in the Special Issue, arranged by topic as pertaining to mitochondrial dysfunction.

Authors Title Topics/Keywords Type
Ahmed et al. [2] Genes The Special Issue opens with three reviews describing aspects of the mitochondrial machinery in the context of maintaining homeostasis and disease [2][3][4]. Ding and Liu [4] together with Ahmed et al. [2] summarize the maintenance and replication of the mitochondrial genome, and discuss how DNA helicases and mtDNA instability affect integrity of the mtDNA, thus contributing to mitochondrial diseases and disorders. Mitochondrial retrograde signaling, specifically the mitochondrial unfolded protein response, involved in proteostasis is reviewed by Arnould et al. [3]. The next five papers review the interconnectedness of mitochondrial dysfunction and protein homeostasis in health, ageing, and diseases [5][6][7][8][9]. Ross et al. [5] discuss the interplay of mitochondrial dysfunction and impairment of the ubiquitin proteasome system in ageing and disease, and provide a hypothetical model to address the heterogeneity often described during ageing. The heterogeneity of skeletal muscle performance in ageing is examined by Crescenzo et al. [6], taking into account the diverse mitochondrial populations present in skeletal muscle. Tricarico et al. [7] focus on a possible link between mitochondrial dysfunction, defective protein prenylation, and the mevalonate pathway, crucial for cholesterol synthesis, with disease. Zhang et al. [8] describe under physiological and pathological conditions the modulators of autophagy that regulate erythropoiesis, a process during which mitochondria and other intracellular organelles are removed. The intersection of mtDNA damage and oxidative stress on age-related vascular dysfunction is presented by Mikhed et al. [9], with particular focus on nicotinamide adenosine dinucleotide phosphate (NADPH) oxidases.
We received several reviews and research articles implicating mitochondria in cardiovascular diseases and ischemia as well as cerebral hypoxia-ischemia [11][12][13][14]. Interestingly, a few of these contributions highlight the role of thyroid hormone [10][11][12]. Vaikus et al. [10] review the diverse effects that thyroid hormone has on mitochondria and energy expenditure, including mitochondrial biogenesis and clinical correlates. Forini et al. [12] discuss possible thyroid hormone triiodothyronine (T3) supplementation to improve mitochondrial function in the context of ischemic heart disease. The same research group also present findings [11] indicating that low T3 levels are correlated with mitochondrial impairments following cardiac ischemia reperfusion injury. Mitochondrial dysfunction is also associated with septic cardiomyopathy, a complication of sepsis, which is a serious condition where the pathogenesis and underlying mechanisms remain unclear, as described by Cimolai et al. [13]. Findings discussed by Babiramani et al. [14] suggest that neonatal cerebral hypoxic-ischemia may alter mitochondrial dynamics, affecting optic atrophy 1 (OPA1). Impaired mitochondrial dynamics have also been described in neurodegenerative diseases, such as Parkinson's disease (PD). Luo et al. [15] review recent literature that support the role of compromised mitochondrial dynamics, mitophagy, and mitochondrial import in PD, and also offer a list of potential therapeutics that target mitochondria. The review by Kim et al. [16] discusses the link between mitochondrial dysfunction and alveolar epithelial cell apoptosis in contributing to age-related lung diseases, as well as how sirtuin family members may constitute therapeutic candidates. Mitochondrial co-factors, such as α-lipoic acid, carnitine, and Coenzyme Q10 have been used to treat mitochondria-associated disorders and diseases, and the results of several clinical trials using these co-factors with and without antioxidants/herbal compounds are systematically presented by Pagano et al. [17].
A few contributions regarding the involvement of mitochondria in cancer and possible therapies were also received [18][19][20][21]. Ever since the "Warburg effect" was described nearly a century ago, mitochondria have been increasingly implicated in cancer biology. Extensive research has revealed notable differences between cancerous and healthy cells, such as altered mitochondrial size, shape, metabolic profiles, membrane potential, as well as elevated levels of mtDNA mutations, mitochondrial transcription factor A (TFAM), and oxidative stress [18,20]. Using these findings to exploit mitochondria, several promising anti-cancer treatments have been developed, but have unfortunately proven to have limitations [18][19][20][21]. Thus, researchers have recently explored alternative strategies as summarized in Modica-Napolitano and Weissig [18] as well as targeting specific microenvironments within tumors as discussed by Zhang et al. [19]. Moreover, the mechanisms by which cancer cells develop drug-resistance are currently being investigated, as reviewed by Kohno et al. [20], and possible means to mitigate the side effects of anti-cancer therapies are also being studied by Wang et al. [21]. Collectively, these contributions focus on mitochondrial mechanisms as an avenue to reveal possible novel interventions in order to combat cancer.
Lastly, but certainly not of least importance, recent studies of the role of mitochondrial function in fertility and oocyte quality have been extensive. Research by Wang et al. [22] demonstrates that androgen receptor knockout mice have poor oocyte maturating rates, impaired ATP production in granulosa cell mitochondria, and impaired mitochondria biogenesis. Additional research is needed to better understand how mitochondrial function may affect fertility and fecundity in order to develop therapeutic approaches.
Overall, the 21 contributions published in the Special Issue illustrate how essential mitochondria are to overall health and success of an organism. The involvement of mitochondria in several biological disciplines, diseases, and disorders, ranging from cancer biology, metabolism, and proteostasis to neurodegenerative and cardiovascular diseases is a testament to their importance and fundamental contributions. We would like to thank all of the authors who contributed their work to the Special Issue. The main objective was to provide ample breadth and depth to depict the interconnectedness of mitochondrial function in ageing and mitochondrial-associated diseases. While the underlying mechanisms linking impaired mitochondria with the ageing process and disease states remain incompletely elucidated, the overall field of mitochondrial biology has made leaps and bounds in only the past two decades. Based on these breakthroughs, new "mito-research" platforms have emerged; for example, mitochondrial function in fertility or in stem cell niches. We remain hopeful that harnessing the power of the mitochondrial network will help us stay healthy.