1. Introduction

Several marine-derived drugs have been highlighted to target mitochondria or mitochondrial signaling pathways and could thus counteract pathological processes in many human diseases, including neurodegenerative diseases, metabolic disorders, cancer proliferation, and metastasis.

The following tsextctions will discussreview the recent advances in biomedical strategies to treat human diseases by harnessing mitochondrial function and/or dynamics using marine resources. It will exclusively focus on biomolecules derived from marine organism and therapeutic strategies that target mitochondria, ranging from mitochondrial biogenesis to mitochondrial degradation (summarized in Table 1 and Table 2 and Figure 1).

2.Conclusions, Challenges, and Future Perspectives

Marine organisms have been used since ancient times as a primary source of therapeutic biomolecules in traditional medicines. As an example, classical texts from the Ancient Greek and Early Byzantine periods describe the therapeutical properties of marine invertebrates, reflecting their common use in medical practice ^[48][121]. The cellular and molecular bases of these therapeutical actions were not known at that time. Nowadays, we know mitochondria are organelles that act as metabolic hubs of cellular signaling production and transmission ^[49][122]. They play a pivotal role in the adaptative responses to complex environmental challenges. Marine organisms are an important source of promising multi-target agents that are able to modulate mitochondrial biology and signaling pathways. Here, rwesearchers reviewed molecules obtained from—and strategies inspired by—marine organisms that may be potentially used to mitigate the symptoms of all the disorders with a mitochondrial pathological basis or involving a mitochondrial-related target protein. Importantly, the marine environment still has to offer a huge and unexplored biodiversity, like that present in deep-sea environments or other very extreme/secluded places, which are species-rich habitats that have been less explored compared to more accessible sites. For instance, due to their adaptation to this extreme environment, deep-sea species have the potential to produce a totally novel group of molecules with potent biological activities, bestowing an unexplored trove of novel therapeutically strategies to alleviate or treat many human diseases, including those caused by altered mitochondrial function or dynamics. Fortunately, the interest in natural products derived from deep-sea species is growing and will continue to do so in the next few years ^[50][123]. Despite yielding great advances in the field, several challenges still remain regarding the identification, characterization, and biomedical translation of novel marine organism-derived compounds acting on mitochondria. It is important to highlight that, often, the molecular mechanisms underlying the beneficial effects of many marine derived molecules that can potentially harness mitochondrial function and act as novel therapeutic entities are still unknown. As an example, a huge number of molecules derived from marine organisms have been described for their antioxidant effect; thus, it is speculated that they are likely acting on mitochondria, but a deeper knowledge on mitochondrial involvement is missing. An exception to this is represented by aurilides—drugs that induce apoptosis by interfering with mitochondrial dynamics and cristae organization—whose molecular mechanism of action has been exhaustively elucidated ^[4][51][27,85]. However, the molecular-resolution knowledge available for these drugs has not resulted in more applications at the translational level. This issue is further complicated because the experimental data on molecular actors regulating mitochondrial dynamics, as well as data on the strong connection linking mitochondrial dynamics and function, are constantly increasing. Therefore, the identification of specific targets regulating mitochondrial biology is a field characterized by constant growth and remodeling ^[49][122]. Another important limitation for translational research in the field, shared by all the bioactive molecules derived from marine organisms, regardless of their molecular mechanism of action, is that the costs of production for these molecules is very high. Consequently, the characterization of the beneficial biomedical properties of many natural compounds derived from marine organisms remains stuck in the preliminary stage of in vitro testing, failing to reach the requirements for the sustainable implementation of in vivo pre-clinical and clinical trials (Figure 2). However, the technical and methodological tools and knowledge needed to produce bioactive metabolites from marine sources on an industrial scale started to emerge during the early 2000s, when research on natural, biomedical compounds attracted interest among scientific communities, as well as pharmaceutical companies. Strategies centered around producing natural compounds from marine bacteria, fungi, or microalgae are based on implementing culture, harvesting, and extraction procedures on a large scale ^[52][124]. This is much more complex for invertebrate sources, where only small amounts of pure compounds are achievable. For these organisms, random sampling directly from the natural environment is not acceptable from an ecological point of view. Moreover, the overall naturally available biomass would be sufficient for industrial demand. Aquaculture of medicine-producing marine invertebrates such as sponges, corals, oysters, or mussels represent a kind of solution to this limitation ^[53][125]. Importantly, the development of chemical synthesis also supported the strategies of production on an industrial scale, thus overcoming the issue of isolation from biomass. Synthetic strategies include the possibility of modifying the molecule of interest and developing derivatives with less complexity and more manageable properties. Moreover, the recently outlined genome sequencing approaches allow for an understanding of the biochemical mechanisms regulating the biosynthesis of specific compounds, helping their synthetic cloning. Synthetic biology approaches can also facilitate the generation of genetically modified microbial cell factories to produce heterologous bioactive molecules, including marine organism-derived compounds ^[54][126]. The process of bringing a drug candidate to the market requires extensive pre-clinical studies and clinical trials to determine the optimal doses, safety, and efficacy of the drug before it is approved by the FDA or the EMA. High costs in terms of money and time explain why only a handful of promising bioactive molecules will eventually reach the market and consumers. From the data gathered in hereinthis review, clearly, the steps connecting the in vitro with the in vivo studies represent the main bottleneck in developing novel therapeutic techniques for mitochondrial illnesses using marine-derived compounds. A strong lack of extensive clinical trials hampers translational investigation in the field. This is the case for many marine-derived compounds that have shown bioactive properties to slow down cancer progression, mainly acting on proliferation. Most studies have been performed in vitro, without taking into account unintended secondary toxic effects on neighboring non-tumor cells or any systemic and non-systemic toxicity. Therefore, we are still far from assessing any safety, dosage, and efficacy issues in human clinical trials and achieving the establishment of these types of compounds for use in precision medicine for patients affected by specific rare diseases. Beyond in vitro 2D cell cultures, new and powerful tools to rapidly assess the potential efficacy of novel drugs are represented by three-dimensional (3D) organoids, which are emerging as promising models for precision medicine. They can be established rapidly and accurately mimic a patient’s response to therapy ^[55][127]. However, the literature describing organoids as a tool to test marine-derived compounds acting on mitochondrial biology is practically non-existent. ThWe researchers are are convinced that using human organoids to create a first step of selection for the most promising marine organism-derived compounds to be used to regulate mitochondrial biology in human pathologies before going into organismic models may represent a useful way to accelerate biomedical translation. This dreviscussionew underscores the importance of focusing on marine organism-derived compounds acting on mitochondrial function to design new treatments against a number of human pathologies with mitochondrial implications. They may act either alone or as adjuvants to gold-standard therapies, exerting synergistic effects in conjunction with conventional drugs. In this field of research, strong efforts should be made to develop well-controlled preclinical trials (in vivo in animal models and/or in vitro in human organoids) as well as clinical trials to assess the huge potential of marine agents in the prevention, treatment, and management of a wide range of human diseases with complex pathologies involving mitochondrial alterations, including neurodegeneration, metabolic diseases, and cancer.