Remembering effortless energy and mental clarity can feel like a distant memory when fatigue becomes the norm.
Shelves full of supplements promise solutions, but they might be missing the foundational problem.
In a recent video, Dr. Ashley Frawley, a board-certified primary care physician, explained why understanding mitochondrial function is critical before supplementing—and revealed that one intervention outperforms every supplement on the market.
She breaks down where energy production actually happens, where it fails, and how popular interventions like NAD, CoQ10, fasting, and cold plunges target specific breakdowns in this cellular machinery.
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Understanding Mitochondrial Architecture
Mitochondria aren’t simple structures. Their shape determines function.
Picture a bean with two distinct walls: a smooth outer membrane and a heavily folded inner membrane. Between them sits what Dr. Frawley calls “the loading dock”—the intermembrane space where critical processes occur.
The outer membrane acts as a porous gateway, allowing fuel, nutrients, and signals to pass through. But chronic inflammation, aging, insulin resistance, and poor metabolic health can stiffen this membrane, blocking essential communication.
Sometimes fatigue doesn’t start because your mitochondria can’t make energy. Sometimes it starts because of this. I call it signal interference.
Fixing the Front Door
Before addressing energy production itself, membrane health requires attention. Dr. Frawley emphasizes changing the lipid composition and reducing structural degradation.
Key interventions include:
- Antioxidants: Berries and colorful vegetables protect membrane integrity
- Omega-3 fatty acids: Particularly EPA and DHA from fish like sardines or quality supplements
- Phosphatidylcholine: The primary structural component of mitochondrial membranes, available as a supplement
The Inner Membrane: Where Energy Is Won or Lost
Unlike its smooth outer counterpart, the inner mitochondrial membrane features extensive folds called cristae—resembling an accordion.
This design is intentional. More surface area means more room for energy-producing machinery, which translates to more ATP production.
Research shows healthy mitochondria display beautifully organized, deep cristae folds. Damaged, stressed, or aged mitochondria show flattened structures—like an accordion that’s lost its shape and can’t make music anymore.
Exercise: The Dominant Intervention
While supplements receive attention, Dr. Frawley emphasizes that consistent exercise represents one of the strongest known signals for improving mitochondrial structure.
Exercise isn’t all about looking good.
This intervention improves cristae formation in ways supplements simply cannot replicate.
The Electron Transport Chain: Your Cellular Assembly Line
Energy production occurs along a five-station assembly line embedded in those folded cristae—the electron transport chain.
Food breaks down into NADH and FADH2—energy delivery trucks carrying hydrogen atoms (one proton, one electron each). At complex one, electrons separate and travel down the chain while protons get pumped across the membrane.
This creates stored potential energy—like pumping water uphill into a reservoir. Eventually, protons rush back through complex five, spinning like a turbine to generate ATP.
Where Supplements Enter
Complex one experiences most age and inflammation-related damage. Several supplements target this vulnerability:
- CoQ10: Shuttles electrons through the assembly line, keeping traffic moving. Particularly important for statin users, since these medications block natural CoQ10 production
- Methylene blue: Rescues electrons stuck in damaged complexes and continues moving them along the chain
- NAD precursors: Support the assembly line by eventually becoming NADH, feeding the electron transport chain
The goal isn’t creating ATP directly—it’s maintaining assembly line efficiency.
The Mitochondrial Matrix: Where Food Becomes Fuel
Inside the inner membrane sits the matrix—where food processing actually occurs through the Krebs cycle (also called citric acid or TCA cycle).
Food enters, gets broken down, and loads up those NADH and FADH2 delivery trucks with cargo for the engines.
This is where NAD supplementation proves useful—not by creating energy from nothing, but by supporting the assembly line that transforms food into usable fuel.
Mitochondrial DNA Damage
Mitochondria contain their own DNA, separate from nuclear DNA. Unfortunately, this becomes a damage accumulation site.
About 1-2% of oxygen moving through the electron transport chain leaks out, creating reactive oxygen species (ROS)—tiny sparks flying off machinery. Small amounts serve useful signaling functions, but excessive stress, poor diet, inadequate sleep, and inflammation create constant sparks that damage mitochondrial DNA, cristae, and the engines themselves.
Aging becomes vicious: more damage creates dysfunction, dysfunction creates more ROS, feeding a destructive cycle.
Quality Control: Mitophagy and Biogenesis
Mitochondria aren’t permanent. Healthy systems constantly remove damaged ones (mitophagy) and build new ones (biogenesis).
Mitophagy—literally “eating mitochondria”—identifies damaged organelles, tags them for removal, breaks them apart, and recycles useful components. Controlled demolition.
Unfortunately, aging, sedentary lifestyles, and metabolic dysfunction slow this cleanup process. Broken mitochondria accumulate, producing inflammatory byproducts and even creating more dysfunctional mitochondria.
Building New Power Plants
Mitochondrial biogenesis—creating new mitochondria—gets controlled largely by PGC1 alpha, the master switch signaling cells to build more power plants.
Popular biohacks activate this pathway: exercise, fasting, cold exposure, elevated NAD levels, and certain peptides.
Urolithin A, produced by gut bacteria when consuming pomegranates, specifically targets mitophagy. Research suggests it helps identify and remove mitochondria that shouldn’t remain, clearing space for new, functional organelles.
Targeting the Right Problem
No single “best” mitochondrial supplement exists—only different interventions targeting specific machinery components.
- Membrane problems: Omega-3s, phosphatidylcholine, improved metabolic health
- Flattened cristae: Exercise (peptides exist but require separate discussion)
- Slow engines: CoQ10, riboflavin, potentially methylene blue (consult your physician)
- Matrix support/NAD deficiency: NMN or other NAD precursors
- Quality control issues: Urolithin A, fasting, cold exposure, exercise
Understanding mitochondrial anatomy transforms random supplementation into targeted intervention.
Dr. Frawley’s key insight? Exercise consistently dominates supplements for structural mitochondrial improvements—the foundation upon which all other interventions build.
Rather than pouring supplements into a system with failing batteries, addressing the root cause—whether membrane dysfunction, damaged cristae, assembly line bottlenecks, or poor quality control—creates lasting energy restoration.
