To truly grasp a disease, it's essential to identify the appropriate level of focus. This is akin to the "forest for the trees" dilemma. Consider Google Maps as an analogy. If you zoom in too much, you'll overlook what you're trying to find. For instance, looking at a map of your neighborhood won't help you locate Greenland. Conversely, zooming out excessively creates the same issue. Imagine trying to find your house by examining a world map. Though it's a good starting point, you won't be able to pinpoint your city, street, or home. It's simply unattainable without the correct scale or level of detail.

The same issue arises in medicine, as human diseases manifest at various levels. For instance, when examining a gunshot injury, if we focus too closely on the victim's genetic composition, we could overlook the critical chest wound that is evidently life-threatening. Conversely, if addressing a genetic condition like Fabry's disease, inspecting the chest wall won't provide much insight into the situation. To understand it, we need to zoom in on the genetic level.

There are diseases that affect the entire body, such as hemorrhage and sepsis. Some conditions target specific organs, like heart failure, strokes, kidney failure, and blindness. Certain diseases occur at the cellular level—examples include myeloma and leukemia. Meanwhile, others are rooted in genetics, such as Duchenne muscular dystrophy and Fabry’s disease. Identifying the appropriate 'level' to investigate is crucial for uncovering the underlying cause of a disease. However, one level has been largely overlooked until recently — the sub-cellular level, which lies between the cellular and genetic spheres.

Different Levels of Human Disease:

• Entire Body
• Individual Organs. Maintain the same atmosphere and style of the text, but avoid rephrasing phrases and HTML tags.
• Each organ's individual cells.
• **Subcellular (Organelles)** Within cells, various structures known as organelles play essential roles. These specialized components, each with their unique functions, contribute to the overall operation and health of the cell.
• Genes.

Our body consists of numerous organs and other types of connective tissue. Each organ is made up of a variety of cells. Inside these cells, there are smaller structures known as organelles, like the mitochondria and endoplasmic reticulum. These tiny components perform specific tasks for the cell, such as producing energy (mitochondria), eliminating waste (lysosomes), and synthesizing proteins (endoplasmic reticulum). The cell's nucleus houses the genetic material, which includes chromosomes and DNA.

We have identified diseases at all levels of biology except for the sub-cellular, organelle level. Is it really possible that organelles never become diseased? That seems highly unlikely. At every level, there are potential issues, and organelles are no different. Mitochondrial dysfunction is gaining increasing attention as a factor in many chronic diseases because these organelles play a crucial role in sensing and integrating environmental signals to initiate adaptive and compensatory responses in cells. In other words, they are essential for detecting external conditions and optimizing the cell’s response. Mitochondrial disease appears to be associated with various diseases involving abnormal growth, such as Alzheimer’s disease and cancer. This connection is logical given that mitochondria are the cell's powerhouses.

Think of an engine as your car’s powerhouse. What part tends to malfunction the most? Typically, it’s the component with the most moving parts, the highest complexity, and the heaviest workload. Therefore, the engine needs regular upkeep to operate properly. In contrast, a simple and seldom-used part with no moving components, like the back seat cushion, requires minimal maintenance and hardly ever fails. You change the oil every few months but rarely spare a thought for the back seat cushion. Similarly, mitochondria are your cells' mini engines and can be just as susceptible to breakdowns as other body parts. Maintaining healthy mitochondria could be a crucial, yet often overlooked, aspect of overall well-being.

So let’s talk mitochondria.

Mitochondrial Dynamics

The most universally recognized function of the mitochondrion is serving as the cell’s powerhouse or energy producer. It produces energy in the form of ATP through a process called oxidative phosphorylation (OxPhos). Organs such as the heart, which tops the list, and the kidneys, which follow closely, have high energy demands and thus are abundant in mitochondria. These organelles are continually adjusting in size and number through processes known as fission (splitting apart) and fusion (merging together). This ongoing change is referred to as mitochondrial dynamics. A single mitochondrion can divide to form two daughter organelles, or conversely, two mitochondria can combine to create a larger one.

Both processes are critical for maintaining mitochondrial health. An excess of fission results in fragmentation, while too much fusion leads to mitochondrial hypertabulation. Achieving the right balance is essential, much like various aspects of life (good and bad, feeding and fasting, yin and yang, resting and activity). The molecular mechanisms behind mitochondrial dynamics were initially identified in yeast, and similar pathways were later found in mammals and humans. Problems with mitochondrial dynamics have been linked to cancer, cardiovascular disease, neurodegenerative diseases, diabetes, and chronic kidney disease. In the case of kidney disease, particularly, excessive fragmentation appears to be the primary concern.

Mitochondrion were initially identified as ‘bioblasts’ by Altmann, and in 1898, Benda noted that these organelles varied in shape, sometimes appearing elongated like threads and other times round like balls. This led to the naming of mitochondrion from the Greek words mitos (thread) and chondrion (granule). In 1914, Lewis observed that “Any one type of mitochondria such as a granule, rod or thread may at times change into any other type,” which we now understand as mitochondrial dynamics.

The quantity of mitochondria is controlled through biogenesis to align with the energy demands of the organ. Similarly to how they are 'born', mitochondria can also be eliminated via mitophagy, which plays a crucial role in quality control. This mitophagy process is closely tied to autophagy, a topic we have covered before.

The sirtuins (SIRT1–7) (previously discussed here), which are another form of cellular nutrient sensors, also play a role in controlling various facets of mitochondrial biogenesis. Elevated AMPK levels (indicating low cellular energy status) additionally work through several intermediaries to boost mitochondrial numbers.

When there's an imbalance in the fission and fusion of mitochondria, it leads to diminished functionality. Beyond being the powerhouse of the cell, mitochondria play a crucial role in programmed cell death, also known as apoptosis. Instead of just letting a cell die when it's no longer needed, the body employs an orderly process. If cells were to simply die and burst open, their contents would spill out, causing inflammation and other types of damage. It’s akin to deciding you don't need an old can of paint anymore. You wouldn't just pour the paint out wherever you stored it; that would create a mess and probably get you in trouble with your partner. Instead, you carefully dispose of it.

The same applies to cells. When a cell gets damaged or becomes unnecessary, it goes through an orderly process of disposing of its contents, which are reabsorbed and can be repurposed. This process, known as apoptosis, plays a crucial role in precisely regulating cell numbers. Additionally, it acts as a key defense mechanism to eliminate unwanted or potentially harmful cells (hello — cancer). So, if the process of apoptosis (a sort of cellular clean-up crew) is impaired, then the result is too much growth.

There are two primary routes for initiating apoptosis: the extrinsic and intrinsic pathways. The intrinsic pathway is triggered by cellular stress. Essentially, if the cell isn't functioning properly, it needs to be eradicated, much like an extra can of paint that isn't needed. This intrinsic pathway is also known as the mitochondrial pathway. Many diseases characterized by excessive growth—such as atherosclerosis (leading to heart attacks and strokes), cancer, and Alzheimer’s disease—are connected to mitochondrial function, where a lack of cellular cleanup may contribute to the problem.

So, how can we maintain healthy mitochondria? The answer lies in AMPK, which acts like a reverse fuel gauge for the cell. When energy reserves drop, AMPK levels rise. This ancient sensor gets activated when cellular energy demands are high. As energy needs increase and reserves fall, AMPK surges and promotes the growth of new mitochondria. As we discussed in our previous post, a rise in AMPK is linked to reduced nutrient sensing, which closely ties to longevity. Certain medications—yes, we’re talking about metformin—can also trigger AMPK, shedding light on its potential role in cancer prevention and its popularity in wellness communities. But you can achieve even more...

Fasting also encourages autophagy and mitophagy, processes that help eliminate old, malfunctioning mitochondria. Thus, the age-old practice of intermittent fasting essentially clears out the old mitochondria while promoting the growth of new ones. Renewing your mitochondria through this method may be significantly important in preventing various diseases that currently lack effective treatments—especially those related to excessive growth. Although metformin might activate AMPK, it does not lower the other nutrient sensors like insulin and mTOR, nor does it promote mitophagy.

So, rather than using a prescription drug off-label and dealing with its inconvenient side effect of diarrhea (seriously, avoid white pants), you could just fast without spending a dime and achieve twice the results. Intermittent fasting. Boom.