The potential of targeting mitochondria-associated programmed cell death for age-related disease treatment

By Dr. Priyom Bose, Ph.D.Reviewed by Danielle Ellis, B.Sc.Aug 28 2023

Scientists have recently reviewed the available literature to examine the critical roles played by mitochondria in maintaining homeostasis. The review summarized the involvement of mitochondria in age-related disease progression and highlighted its potential as a therapeutic target of these diseases. This review has been published in Experimental & Molecular Medicine.

Structure and functions of mitochondria

Mitochondria is a cytoplasmic organelle in most eukaryotic cells and is enclosed by two phospholipid membranes: the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM). These membranes separate functionally compartmentalized structures, i.e., matrix and intermembrane space. Mitochondria contain a unique genetic code, mitochondrial DNA (mtDNA). 

During evolution, most mitochondrial genes were lost or translocated to nuclei. However, genes that remained in mtDNA encode for essential translational apparatus, i.e., ribosomal RNAs and transfer RNAs. In addition, these genes also encode proteins that are key components of oxidative phosphorylation system (OXPHOS) complexes embedded in the IMM.

The key functions of mitochondria are energy production, fatty acid oxidation, iron–sulfur cluster biosynthesis, thermogenesis, and cellular signaling. Since mitochondria are a cell powerhouse, it harbors many catabolic pathways. Mitochondria regulates signaling pathways through cytochrome c (cyt c) release and caspase activation, which leads to immune responses and programmed cell death (PCD) activation.

Furthermore, it also modulates the levels of intracellular molecules, such as reactive oxygen species (ROS) and calcium ions. Different mitochondrial quality control (MQC) networks are present to maintain mitochondrial functionality and ensure homeostasis.

Mitochondria-associated programmed cell death

Mitochondria are associated with a diverse cell death-promoting signaling convergence, which includes both apoptosis PCD and nonapoptotic PCD. Apoptosis is the key driver of homeostasis and development of eukaryotic organisms. Some of the non-apoptotic PCDs include necroptosis, pyroptosis, parthanatos, and ferroptosis.

PCD is not only an essential feature for the development of multicellular organisms, it also causes degenerative diseases. Apoptosis is characterized by cell shrinkage, karyorrhexis, and nuclear pyknosis, which occurs in response to stimuli (e.g., hypoxic, ischemic, immune reaction, and infectious factors). Apoptotic bodies are eventually engulfed by phagocytic cells. In almost every organ system, apoptosis plays a critical role in physiological homeostasis.

Apoptosis is a genetically specified program that involves multiple extrinsic and intrinsic molecular pathways. The extrinsic pathway, also known as the death receptor pathway, causes apoptosis when extracellular ligands bind cognate transmembrane death receptors. This event triggers a downstream caspase cascade, leading to apoptotic PCD.

The intrinsic molecular pathways are also known as mitochondrial or Bcl-2-regulated pathways because they require a bid for apoptosis. This mechanism is associated with the activation of caspase-8, which induces Bid activity.

Apoptosis and necroptosis differ in many ways. For instance, necroptotic cells are associated with cellular disruption, nuclear condensation, DNA hydrolysis, chromatin digestion, and eventually cell lysis. Tumor necrosis factor (TNFα) plays a key role in driving necroptosis. 

Ferroptosis is an oxidation-related PCD that is driven by iron-dependent lipid peroxidation. Pyroptosis is another type of non-apoptotic PCD driven by inflammation and subsequent plasma membrane permeabilization, causing cellular leakage. Recently, parthanatos has been characterized as PCD triggered by hyperactivation of DNA damage-responsive enzymes, such as poly (ADP-ribose) polymerase 1 (PARP1).

Age-related diseases linked to mitochondrial cell death

Several studies have indicated the role of mitochondrion-associated PCD in the pathogenesis of many organs. Mitochondria dysfunction is a key contributing factor to aging and various age-related diseases (e.g., cardiovascular, neurodegenerative, and metabolic diseases).

Mitochondrion-associated PCD has been linked to the incidence of cancer. An elevated level of ROS triggers apoptosis in cancer cells. A significantly high level of ROS disrupts mitochondrial functions, ultimately activating intrinsic apoptosis pathways. An excessive ROS level also triggers necroptosis, activating inflammatory and anticancer immune responses. 

Mitochondrial cell death establishes a barrier that complements MQC in defense against cancers. This function is associated with the clearance of cancer cells. Taken together, mitochondrial cell death was found to be intricately involved in cancer eradication and tumor cell immune evasion.

Several neurodegenerative diseases (e.g., Alzheimer’s disease-AD) have been associated with different mechanisms linked to mitochondrial dysfunction, such as apoptosis and ROS generation. Neurons largely rely on mitochondria for energy and Ca²⁺ buffering. Therefore, these cells are vulnerable to mitochondrial abnormalities.

In the context of AD, amyloid β (Aβ) accumulation, which is the key initiator of this disease, induces mitochondrial Ca²⁺ overload along with increasing hyperphosphorylated tau protein levels, ultimately triggering apoptosis. 

Many studies have indicated that mitochondrion-associated PCD is the main regulator of cardiovascular diseases, such as atherosclerosis, heart failure, and aneurysms. However, apoptosis is not the only mode of cell death in these diseases; necroptosis induced by oxidative stress or ischemia/reperfusion also leads to heart failure. In the case of metabolic disease, apoptosis was the key mechanism linked with β-cell loss in Type 1 diabetes, and a reduced β-cell population leads to Type 2 diabetes.

Considering the above findings, future studies must focus on developing PCD-based therapy and conducting clinical trials to validate the findings.